(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
International Bureau
(43) International Publication Date
31 August 2006 (31.08.2006)
PCT
(10) International Publication Number
WO 2006/091394 A2
(51) International Patent Classification:
A61K 31/4745 (2006.01)
(21) International Application Number:
PCT/US2006/004713
(22) International Filing Date:
10 February 2006 (10.02.2006)
(25) Filing Language: English
(26) Publication Language: English
(30) Priority Data:
60/652,239 1 1 February 2005 (1 1 .02.2005) US
(71) Applicant (for all designated States except i/S): 3M
INNOVATIVE PROPERTIES COMPANY [US/US];
3M Center, Post Office Box 33427, Saint Paul, Minnesota
55133-3427 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): RICE, Michael, J.
[US/US]; 3M Center, Post Office Box 33427, Saint Paul,
Minnesota 55133-3427 (US). HARALDSON, Chad,
A. [US/US]; 3M Center, Post Office Box 33427, Saint
Paul, Minnesota 55133-3427 (US). GERSTER, John,
F. [US/US]; 3M Center, Post Office Box 33427, Saint
Paul, Minnesota 55133-3427 (US). WURST, Joshua, R.
[US/US]; 3M Center, Post Office Box 33427, Saint Paul,
Minnesota 55133-3427 (US). HEPPNER, Philip, D.
[US/US]; 3M Center, Post Office Box 33427, Saint Paul,
Minnesota 55133-3427 (US). KSH1RSAGAR, Tushar,
A. [IN/US]; 3M Center, Post Office Box 33427, Saint
Paul, Minnesota 55133-3427 (US). MERRILL, Bryon,
A. [US/US]; 3M Center, Post Office Box 33427, Saint
Paul, Minnesota 55133-3427 (US).
(74) Agents: ERSFELD, Dean, A. et aL; 3M Center, Office
of Intellectual Property Counsel, Post Office Box 33427,
Saint Paul, Minnesota 55133-3427 (US).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, Nl,
NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US,
UZ, VC, VN, YU, ZA, ZM, ZW.
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
GN, GQ, GW, ML, MR, NE, SN, TD, TG).
Declarations under Rule 4.17:
— as to applicant's entitlement to apply for and be granted a
patent (Rule 4.17(H))
— as to the applicant s entitlement to claim the priority of the
earlier application (Rule 4A7(iii))
Published:
— without international search report and to be republished
upon receipt of that report
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations " appearing at the begin-
ning of each regular issue of the PCT Gazette.
= (54) Title: SUBSTITUTED IMIDAZOQU1NOL1NES AND IMIDAZONAPHTHYRIDINES
(57) Abstract: Imidazoquinolines and imidazonaphthyridines with a substituent containing a functional group, e.g., an amide,
^= sulfonamide, urea, or heterocyclyl group, at the 6, 7, 8, or 9-position, pharmaceutical compositions containing the compounds, in-
^ lermediates, methods of making and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis
in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.
Tf
m
i— i
OS
©
o
WO 2006/091394
PCT/US2006/004713
SUBSTITUTED IMIDAZOQUINOLINES AND IMIDAZONAPHTHYRIDINES
CROSS REFERENCE TO RELATED APPLICATIONS
The present invention claims priority to U.S. Provisional Application Serial No.
60/652239, filed February 1 1, 2005, which is incorporated herein by reference.
Certain compounds have been found to be useful as immune response modifiers
(IRMs), rendering them useful in the treatment of a variety of disorders. However, there
continues to be interest in and a need for compounds that have the ability to modulate the
immune response, by induction of cytokine biosynthesis or other mechanisms.
The present invention provides a new class of compounds that are useful in
inducing cytokine biosynthesis in animals. Such compounds are of the following Formula
wherein R A , Rb, R', and R" are as defined below.
The compounds of Formula I are useful as immune response modifiers due to their
ability to induce cytokine biosynthesis (e.g., induces the synthesis of at least one cytokine)
and otherwise modulate the immune response when administered to animals. This makes
the compounds useful in the treatment of a variety of conditions such as viral diseases and
tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing an
effective amount of a compound of Formula I and methods of inducing cytokine
biosynthesis in an animal, treating a viral infection or disease and/or treating a neoplastic
BACKGROUND
SUMMARY
1
WO 2006/091394
PCT/US2006/004713
10
disease in an animal by administering an effective amount of a compound of Formula I to
the animal.
In addition, methods of synthesizing compounds of Formula I and intermediates
useful in the synthesis of these compounds are provided.
As used herein, "a," "an," "the," "at least one," and "one or more" are used
interchangeably.
The terms "comprises" and variations thereof do not have a limiting meaning
where these terms appear in the description and claims.
The above summary of the present invention is not intended to describe each
disclosed embodiment or every implementation of the present invention. The description
that follows more particularly exemplifies illustrative embodiments. In several places
throughout the description, guidance is provided through lists of examples, which
examples can be used in various combinations. In each instance, the recited list serves
only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION
The present invention provides compounds of the following Formulas I through
VII:
NH,
20
I
NH.
>-R 2
II
2
WO 2006/091394
PCT/US2006/004713
wherein R A , Rb, R r , R", R, Ri, R2, R3, G, and n are as defined below;
and pharmaceutical^ acceptable salts thereof.
In one embodiment, the present invention provides a compound of Formula I:
WO 2006/091394
PCI7US2006/004713
V-R'
wherein:
R A and Rb taken together form a fused benzene ring or fused pyridine ring wherein
5 the benzene ring or pyridine ring is substituted by one R3 group, or substituted by one R3
group and one R group;
15 trifiuoromethyl;
R and R" are independently selected from the group consisting of hydrogen and
non-interfering substitutents;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
20 with one or more -O- groups;
R3 is selected from the group consisting of:
10
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R 5 ,
-Z-Het,
-Z-Hef-Ri, and
-Z-Het'- Y-R4;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
Y is selected from the group consisting of:
-0-,
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
25
-C(R6)-,
-C(R6)-0-,
-0-C(Rfi)-,
-0-C(0)-0-,
,N(R 8 )-Q-,
4
WO 2006/091394
PCT/US2006/004713
-C(R 6 )-N(R 8 )-,
-0-C(R6>N(R 8 )- 5
-C(R 6 )-N(OR 9 )-,
+ N-Q —
5
Het is heterocyclyl which can be unsubstituted or substituted by one or more
10 substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het 1 is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
1 5 haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
20 or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
5
WO 2006/091394
PCT7US2006/004713
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
5 heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
10
R6 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
15 R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -CH 2 -, -C(O)-, -S(0)o- 2 -, and
-N(R4>;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(0) 2 -,
20 -C(R6)-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R6)-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of-C(R 6 )-, -0-C(R 6 )-, -N(R 8 )-C(R^)-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and -8(0^-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
25 with the proviso that when R' is heterocyclyl, then heterocyclyl is attached to the
imidazo ring by an atom in heterocyclyl other than a nitrogen atom; and
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-R4 or -Z-Y-X-Y-R,, and the Y group bonded to Z is -0-,
6
WO 2006/091394
PCT/US2006/004713
-0-C(R6)-, -OC(0)-0-, -0~C(R 6 )-N(R 8 )-,
— V-N
wherein V is
— N-C(R 6 )-N-W- — N
-0-C(R*)-, R 7 >0 r
or
R3 is -Z-R 5 , and R5 is
-(CH 2 ) a ^
(CH 2 ) b ~^
A
wherein V is
~OC(R6)-; or
R 3 is -Z-Het, -Z-Hef-R4, or -Z-Het r - Y-R4, and Z is attached to a nitrogen
atom in Het or Het 1 ;
and with the further proviso that R3 is other than -NH2;
or a pharmaceutical^ acceptable salt thereof
In another embodiment, the present invention provides a compound of Formula II:
R3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R 5 ,
-Z-Het,
-Z-Het'-R*, and
-Z-Het'-Y-R4;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
n is 0 or 1;
Ri is selected from the group consisting of:
NH,
II
wherein:
WO 2006/091394
PCTAJS2006/004713
-R4,
-X-R4,
-X-Y-R,,
-X-Y-X-Y-R4, and
-X-R 5 ;
R2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R,, and
-X-R 5 ;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-o-,
-S(0)o- 2 -,
-S(0)2-N(R 8 )- 5
-C(Rfi)-,
-C(R6)-0-,
-0-C(R5)-,
-0-C(O)-0-,
-N(R 8 )-Q-,
-C(R0-N(R 8 )-,
-0-C(R 6 )-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
-C *N-Q —
8
WO 2006/091394
PCT/US2006/004713
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
5 haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het 1 is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
10 dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
15 R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
20 can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
25 oxo;
R 5 is selected from the group consisting of:
WO 2006/091394 PCT/US2006/004713
-N-C(R 6 ) ~N-S(0) 2 _ V -|( \ -f N-C(R 6 )-N A
9 9 9 ******
-ON;
R<5 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
5 Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
A is selected from the group consisting of -0-, -CH 2 -, -C(O)-, -S(0)o-2-, and
10 -N(R4>;
Q is selected from the group consisting of a bond, -C(Rfi)-, -C(R6)-C(R^)-, -S(0)2-,
-C(R 6 )-N(R g )-W-, -S(0) 2 -N(Rg>, -C(R6,-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of -C(R$)-, -0-C(R$)-, -N(Rg)-C(R6)-, and
-S(0) 2 -;
15 W is selected from the group consisting of a bond, -C(0)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that when Ri is R4, and R4 is heterocyclyl, then heterocyclyl is
attached to the imidazo ring by an atom in heterocyclyl other than a nitrogen atom; and
with the proviso that Z is other than a bond when:
20 R 3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
—V-N
V R
-0-C(R6)-, -OC(0)-0-, -0-C(R 6 )-N(R 8 )-, 10 wherein V is
— N-C(R 6 )-N-W- — N— R 7 — N-Q—
-O-CCRfi)-, ^ R 7 , or ^ R 7 ; or
R 3 is -Z-R 5 , and R 5 is
^(CH 2 ) a x
R y , R? ,or (CH 2 ) b -^ wherein Vis
N-C(R 6 ) -N-S(0) 2 v a
25 -O-C(R<0-; or
10
WO 2006/091394
PCT/US2006/004713
R 3 is -Z-Het, -Z-Hef-Rj, or -Z-Hef-Y-Rj, and Z is attached to a nitrogen
atom in Het or Het';
and with the further proviso that R3 is other than -NH2;
or a pharmaceutical^ acceptable salt thereof.
In another embodiment, the present invention provides a compound selected from
the group consisting Formulas III, IV, V, and VI:
, and
in
IV
10 VI
wherein:
R3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
15 -Z-R 5 ,
-Z-Het,
-Z-Het'-Ri, and
-Z-Het'-Y-R*;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
20 trifluoromethyl;
n is 0 or 1 ;
Rj is selected from the group consisting of:
-Rt,
-X-R4,
25 -X-Y-Rt,
11
WO 2006/091394
PC17US2006/004713
-X-Y-X-Y-R4, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-0-,
-S(0)o- 2 -,
-S(0)2-N(R 8 >,
-C(R6)-,
-C(R 6 )-0-,
-0-C(R 6 >,
-0-C(0)-0-,
-N(Rs)-Q-,
-C(R6)-N(R8)-,
-0-C(R6)-N(R8)-,
-C(R6)-N(OR 9 )-,
-C N-Q —
•10
, and
12
WO 2006/091394
PCT7US2006/004713
N-C(R 6 )-N
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyallcylenyl,
amino, alkylamino, dialkylamino, and oxo;
Hef is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
— N— C(R 6 ) -N-S(O),
P
(CH 2 ) b -^
N-C(R 6 )-N
and
-ON;
R6 is selected from the group consisting of =0 and =S;
13
WO 2006/091394 PCT/US2006/004713
R 7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
5 Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -CH 2 -, -C(O)-, -S(0)o-2~, and
-N(R4)S
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R$)-, -S(0)2-,
-C(R 6 )-N(R 8 )-W-, ~S(0) 2 -N(R 8 )-, -CXR^-O-, and -C(R 6 )-N(OR 9 )s
10 V is selected from the group consisting of -C(R6)-> -0-C(R6)-, -N(R8)-C(R6)-, and
-S(0) 2 s
W is selected from the group consisting of a bond, -C(O)-, and -S(0)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that Z is other than a bond when:
15 R 3 is -Z-Y-R, or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
—V-N
-O-CCR*)-, -OC(0)-0-, -0-C(R 6 )-N(R 8 >, * 10 wherein V is
— N-C(R 0 )-N-W- — N— R 7 -N-Q—
-0-C(R 6 )-, ^ R 7 , or R 7 ; or
R 3 is -Z-R 5 , and R 5 is
/-(CH 2 ) a .
~N-C(R 6 ) -N-S(0) 2 - V -& \
R 7 , R7 ,or (CH^-- 7 wherein Vis
20 -0-C(R6)s or
R 3 is -Z-Het, -Z-Het'-R4, or -Z-Het'-Y-R,, and Z is attached to a nitrogen
atom in Het or Het';
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of Formula
25 VII, which is a prodrug:
14
WO 2006/091394
PCT/US2006/004713
wherein:
G is selected from the group consisting of:
-C(0)-R*",
a-aminoacyl,
a-aminoacyl-a-aminoacyl,
-C(0)-0-R"\
-C(0)-N(R m, )R"',
-C(=NY0-R ,M ,
-CH(OH)-C(0)-OY h
-CH(OC M alkyl)Y 0 ,
-CH 2 Y 2 , and
-CH(CH 3 )Y 2 ;
R m and R"" are independently selected from the group consisting of C M o alkyl,
C3-7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by
one or more substituents independently selected from the group consisting of halogen,
hydroxy, nitro, cyano, carboxy, Ci-e alkyl, Cm alkoxy, aryl, heteroaryl, aryl-Ci-4 alkylenyl,
heteroaryl-Ci.4 alkylenyl, halo-Ci. 4 alkylenyl, halo-CM alkoxy, -0-C(0)-CH3,
-C(0)-0-CH 3 , -C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 , with the proviso
that R"" can also be hydrogen;
a-aminoacyl is an a-aminoacyl group derived from an a-amino acid selected from
the group consisting of racemic, D-, and L-amino acids;
Yi is selected from the group consisting of hydrogen, Ci_6 alkyl, and benzyl;
Yo is selected from the group consisting of Cm alkyl, carboxy-Cu6 alkylenyl,
amino-CM alkylenyl, mono-N-Ci-6 alkylamino-Ci-4 alkylenyl, and
di-N,N-Cu6 alkylamino-Ci-4 alkylenyl;
Y 2 is selected from the group consisting of mono-N-C 1-6 alky lamino,
15
WO 2006/091394
PCT/US2006/004713
di-N,N-Ci^alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, and
4-Cm alkylpiperazin-l-yl;
Ra and Rb are defined as in Formula I above;
R] and R2 are as defined as in Formula II above;
5 or a pharmaceutical^ acceptable salt thereof.
In one embodiment, the present invention provides an intermediate compound of
Formula X:
X
10 wherein:
R3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
~Z-R 5 ,
15 -Z-Het,
-Z-Het'-R4, and
-Z-Het*-Y-R4;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
20 nisOorl;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
25 .X-Y-X-Y-R4, and
-X-R5;
R2 is selected from the group consisting of:
-R4,
-X-R4,
16
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-X-Y-R4, and
-X-R 5 ;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-0-,
-s(oy 2 -,
-SCO^-NCRs)-,
-C(R6>,
-cm-o-,
-0-C(R 6 )-,
-0-C(0)-0-,
-N(Rg)-Q-,
-C(R6)-N(R 8 )-,
-0-C(R,5)-N(R«>,
-C(R6)-N(OR9>,
_/LN-Q —
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
17
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haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Hef is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
5 haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
10 or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
15 heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
20 (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
-N-C(Re) -N-S(0) 2 _ V -
-(CH 2 ) a ^
A
(CH 2 ) b -^
N-C(R 6 )-N
and
-ON;
25
R$ is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
30
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
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A is selected from the group consisting of -0-, -CH 2 -, -C(O)-, -S(0)o-2-, and
-N(R4)-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R<s)-, -S(0)2-,
-C(R6)-N(R8)-W-, -S(0) 2 -N(R 8 )-, -C(R 6 )-0-, and -C(R6)-N(OR 9 )s
V is selected from the group consisting of -C(Re)-, -0-C(R 6 )-, -N(R8)-C(R6)-, and
-S(0) 2S
W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
— V-N
-0-C(R6)-, -OC(0)-0-, -0-C(R<5)-N(R8)-, 10 wherein V is
-N-C(R 6 )-N-W- — N— R 7 — N-Q—
-O-CCRe)-, ^ R 7 , or ^ R ? ; or
R3 is -Z-R5, and R5 is
/-(CH 2 ) a >.
-N-C(R 6 ) -N-S(0) 2 — v-fQ \
R 7 , R? ,or (CH 2 ) b — ^ wherein Vis
-0-C(Re)-; or
R 3 is -Z-Het, -Z-Hef-Ri, or -Z-Het'-Y-R,, and Z is attached to a nitrogen
atom in Het or Hetf;
and with the further proviso that R3 is other than -NH 2 ;
or a pharmaceutical^ acceptable salt thereof.
In one embodiment, the present invention provides an intermediate compound of
Formula XI:
-N
XI
wherein:
19
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R3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-Rs,
5 -Z-Het,
-Z-Het'-R4, and
-Z-Hef-Y-R4;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
10 nisOorl;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R,,
15 -X-Y-X-Y-R,, and
-X-R 5 ;
R2 is selected from the group consisting of:
-R4,
-X-R4,
20 -X-Y-R,, and
-X-R 5 ;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
25 Y is selected from the group consisting of:
-0-,
-S(0)o- 2 -,
-S(0) 2 -N(Rs)-,
-C(R6)-,
30 -C(R6)-0-,
-0-C(R5)-,
-0-C(0)-0-,
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-N(Rs)-Q-,
-C(R6)-N(R 8 )-,
-O-C^-NCRg)-,
-C(R 6 )-N(OR 9 K
J- N-Q —
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het 1 is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
21
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alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
-N-C(R 6 ) ~N-S(0) 2 _ v -^, \ -f N-C(R 6 )-N A
-n— ^k 6 ; y »w 2 — v-n a t ~ v 6/ \
A
10 R / , , X (CH 2 ) b ^, md
-C=N;
R$ is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
1 5 hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -CH2-, -C(O)-, -S(0)o- 2 -, and
-N(R4)-;
20 Q is selected from the group consisting of a bond, -C(R$)-, -C(R6)-C(R6)-, -S(0)2-,
-C(R6>N(R 8 )-W- 3 -S(0)2-N(R 8 )-, -C(R*)-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of -C(R6>, -0-C(R6)-, -N(Rg)-C(R6)-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -; and
25 a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
—V-N
Vr
-0-C(R6)-, -OC(0)-0-, -0-C(R6)-N(Rg)-, 10 wherein V is
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— N-C(R 6 )-N-W- — N— R 7 -N-Q—
-0-C(R6)-, Rl , or ^ R ? ; 0 r
R3 is -Z-R5, and R5 is
— N — C(Rg) -N-S(0) 2 _ v _tf \
C J V J \
R 7 , R7 ,or (CH 2 ) b ^ wherein Vis
-0-C(R 6 )-; or
R 3 is -Z-Het, -Z-Het'-R*, or -Z-Hef-Y-R4 5 and Z is attached to a nitrogen
atom in Het or Het 1 ;
or a pharmaceutical!;/ acceptable salt thereof.
Herein, "non-interfering" means that the ability of the compound or salt, which
includes a non-interfering substituent, to modulate the biosynthesis of one or more
cytokines is not destroyed by the non-interfering substitutent For certain embodiments, R'
is hydrogen or a non-interfering substituent. Illustrative non-interfering R' groups include
those described above for Rj. For certain embodiments, R" is hydrogen or a non-
interfering substituent. Illustrative non-interfering R M groups include those described
above for R 2 .
As used herein, the terms "alkyl," "alkenyl," "alkynyl" and the prefix M alk-" are
inclusive of both straight chain and branched chain groups and of cyclic groups, e.g.,
cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to
20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl
groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a
total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4
carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3
to 1 0 ring carbon atoms. Exemplary cyclic groups include cyclopropyl,
cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted
bornyl, norbornyl, and norbornenyl.
Unless otherwise specified, "alkylene," "alkenylene," and "alkynylene" are the
divalent forms of the "alkyl," "alkenyl," and "alkynyl" groups defined above. The terms,
"alkylenyl," "alkenylenyl," and "alkynylenyl" are use when "alkylene," "alkenylene," and
23
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"alkynylene," respectively, are substituted. For example, an arylalkylenyl group
comprises an alkylene moiety to which an aryl group is attached.
The term "haloalkyl" is inclusive of groups that are substituted by one or more
halogen atoms, including perfluorinated groups. This is also true of other groups that
5 include the prefix "halo-." Examples of suitable haloalkyl groups are chloromethyl,
trifluoromethyl, and the like.
The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.
Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
Unless otherwise indicated, the term "heteroatom" refers to the atoms O, S, or N.
10 The term "heteroaryl" includes aromatic rings or ring systems that contain at least
one ring heteroatom (e.g., 0, S, N). In some embodiments, the term "heteroaryl" includes
a ring or ring system that contains 2-12 carbon atoms, 1-3 rings, 1-4 heteroatoms, and O,
S, and N as the heteroatoms. Exemplary heteroaryl groups include fiiryl, thienyl, pyridyl,
quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl,
15 pyrazolyl, oxazolyl, thiazolyl, benzofiiranyl, benzothiophenyl, carbazolyl, benzoxazolyl,
pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl,
isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl,
tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at
20 least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially
unsaturated derivatives of the above mentioned heteroaryl groups. In some embodiments,
the term "heterocyclyl" includes a ring or ring system that contains 2-12 carbon atoms, 1-3
rings, 1-4 heteroatoms, and O, S, and N as the heteroatoms. Exemplary heterocyclyl
groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1,1-
25 dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl,
isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1,4-
oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl,
dihydroisoquinolin-( 1 H)-y 1, octahydroisoquinolin-( 1 //)-yl, dihydroquinolin-(2//)-y 1,
octahydroquinolin-(2#)-yl, dihydro-l//-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, 1,1-
30 dioxidotetrahydrothien-3-yl, 2-oxopyrrolidin-l-yl, and the like.
The term "heterocyclyl" includes bicylic and tricyclic heterocyclic ring systems.
Such ring systems include fused and/or bridged rings and spiro rings. Fused rings can
24
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include, in addition to a saturated or partially saturated ring, an aromatic ring, for example,
a benzene ring. Spiro rings include two rings joined by one spiro atom and three rings
joined by two spiro atoms.
When "heterocyclyl" contains a nitrogen atom, the point of attachment of the
5 heterocyclyl group may be the nitrogen atom unless otherwise indicated.
The terms "arylene," "heteroarylene," and "heterocyclylene" are the divalent forms
of the "aryl," "heteroaryl," and "heterocyclyl" groups defined above. The terms,
"arylenyl," "heteroarylenyl," and "heterocyclylenyl" are used when "arylene,"
"heteroarylene," and "heterocyclylene," respectively, are substituted. For example, an
10 alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
When a group (or substituent or variable) is present more than once in any Formula
described herein, each group (or substituent or variable) is independently selected, whether
explicitly stated or not. For example, for the formula -N(R8)-C(R^)»N(Rs)- each Rs group
is independently selected. In another example, when an R2 and an R3 group both contain
15 an R4 group, each R4 group is independently selected. In a further example, when more
than one Y group is present and each Y group contains one or more Rg groups, then each
Y group is independently selected, and each Rg group is independently selected.
The invention is inclusive of the compounds described herein in any of their
pharmaceutical^ acceptable forms, including isomers (e.g., diastereomers and
20 enantiomers), salts, solvates, polymorphs, prodrugs, and the like. In particular, if a
compound is optically active, the invention specifically includes each of the compound's
enantiomers as well as racemic mixtures of the enantiomers. It should be understood that
the term "compound" includes any or all of such forms, whether explicitly stated or not
(although at times, "salts" are explicitly stated).
25 The term "prodrug" means a compound that can be transformed in vivo to yield an
immune response modifying compound, including any of the salt, solvated, polymorphic,
or isomeric forms described above. The prodrug, itself, may be an immune response
modifying compound, including any of the salt, solvated, polymorphic, or isomeric forms
described above. The transformation may occur by various mechanisms, such as through
30 a chemical (e.g., solvolysis or hydrolysis, for example, in the blood) or enzymatic
biotransformation. A discussion of the use of prodrugs is provided by T. Higuchi and W.
Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series,
25
WO 2006/091394 PCT/US2006/004713
and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987.
For any of the compounds presented herein, each one of the following variables
(e.g., Z, Y, X, R A , R B , R, Ri, R2> R3, Q, n, and so on) in any of its embodiments can be
5 combined with any one or more of the other variables in any of their embodiments and
associated with any one of the formulas described herein, as would be understood by one
of skill in the art. Each of the resulting combinations of variables is an embodiment of the
present invention.
For certain embodiments of Formulas I or VII, R A and R B taken together form a
10 fused benzene ring or fused pyridine ring wherein the benzene ring or pyridine ring is
substituted by one R3 group, or substituted by one R 3 group and one R group.
For certain embodiments of Formulas I or VII, R A and R B are taken together to
form a fused benzene ring wherein the benzene ring is substituted by one R3 group, or
substituted by one R3 group and one R group;. In certain of these embodiments, the fused
1 5 benzene ring is substituted by one R3 group.
For certain embodiments of Formulas I or VII, R A and R B are taken together to
form a fused pyridine ring wherein the pyridine ring is substituted by one R3 group, or
substituted by one R3 group and one R group. In certain of these embodiments, the fused
pyridine ring is substituted by one R 3 group.
20 For certain embodiments, including any one of the above embodiments of Formula
I, R' is Ri; wherein Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
25 -X-Y-X-Y-R4, and
-X-R 5 ;
with the proviso that when R\ is R4, and R» is heterocyclyl, then heterocyclyl is
attached to the imidazo ring by an atom in heterocyclyl other than a nitrogen atom.
For certain embodiments, including any one of the above embodiments of Formula
30 I, R" is R2; wherein R 2 is selected from the group consisting of:
-R4,
-X-R4,
26
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-X-Y-R4, and
-X-R5.
For certain embodiments, the compound selected from the group consisting of
Formulas III, IV, V, and VI, or a pharmaceutical^ acceptable salt thereof is the compound
of Formula III:
or a pharmaceutical^ acceptable salt thereof.
For certain embodiments, n is 0 in the above embodiments of Formulas II, III, IV,
V, or VI.
For certain embodiments, R is selected from the group consisting of alkyl, alkoxy,
hydroxy, halogen, and trifluoromethyl.
For certain embodiments, R' is hydrogen or a non-interfering substituent
For certain embodiments, R' is a non-interfereing substituent.
For certain embodiments, R is Ri; wherein Ri is selected from the group
consisting of -R4, -X-R4, -X-Y-R4, -X-Y-X-Y-R4, and -X-R 5 .
For certain embodiments, R is Ri; wherein Ri is selected from the group
consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, dihydroxyalkyl,
alkoxyalkylenyl, alkylsulfonylalkylenyl, -X-Y-R4, -X-R 5 , and heterocyclylalkylenyl;
wherein the heterocyclyl of the heterocyclylalkylenyl group is optionally substituted by
one or more alkyl groups; wherein X is alkylene; Y is -N(Rg)-C(0)-, -N(R 8 )-S(0) 2 -,
-N(R 8 )-C(0)-N(R 8 )-, or
NH.
Ill
N-Q —
; R4 is alkyl, aryl, or heteroaryl; and R5 is
^(CH 2 ) a
-N-C(R 6 ) -N-S(0) 2 _ N(R8) - C (0)-N i
For certain embodiments, R" is hydrogen or a non-interfering substituent.
27
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For certain embodiments, R" is a non-interfering substituent.
For certain embodiments, R" is R2; wherein R2 is selected from the group
consisting of -R4, -X-R4, -X-Y'-Ri, and -X-R 5 '.
For certain embodiments, R" is R2; wherein R2 is selected from the group
consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
For certain embodiments, Rj is selected from the group consisting of -R4, -X-R4,
-X-Y-R4, -X-Y-X-Y-R,, and -X-R 5 .
For certain embodiments, including any one of the above embodiments wherein R\
is present, Ri is selected from the group consisting of alkyl, arylalkylenyl,
aryloxyalkylenyl, hydroxyalkyl, dihydroxyalkyl, alkoxyalkylenyl, alkylsulfonylalkylenyl,
-X-Y-R4, -X-R5, and heterocyclylalkylenyl; wherein the heterocyclyl of the
heterocyclylalkylenyl group is optionally substituted by one or more alkyl groups; wherein
X is alkylene; Y is -N(R 8 )-C(0)-, -N(R 8 )-S(0) 2 -, -N(R*)-C(0)-N(R 8 )- 5 or
For certain embodiments, including any one of the above embodiments wherein Ri
is present, Ri is selected from the group consisting of 2-hydroxy-2-methylpropyl, 2-
methylpropyl, propyl, ethyl, methyl, 2,3-dihydroxypropyl, 3-isopropoxypropyl, 2-
phenoxyethyl, 4-[(methylsulfonyl)amino]butyl, 2-methyl-2[(methylsulfonyl)amino]propyl,
2-(acety lamino)-2-methylpropyl, 2- { [(isopropylamino)carbonyl]amino) -2-methylpropyl,
4-{ [(isopropylamino)carbonyl]amino}butyl, 4-(l , 1 -dioxidoisothiazolidin-2-yl)butyl,
tetrahydro-2//-pyran-4-yImethyl, and (2,2-dimethyl-l ,3-dioxolan-4-yl)methyl.
For certain embodiments, including any one of the above embodiments wherein Ri
is present except where excluded, R\ is selected from the group consisting of 2-
[(methylsulfonyl)amino]ethyl, 2-(l , l-dioxidoisothiazolidin-2-yl)ethyl, 3-(2-oxopyrrolidin-
l-yl)propyl, and 2-{[(isopropylamino)carbonyl]amino}ethyl.
For certain embodiments of Formulas III, IV, V, VI, or XI, when Rj is R4, and R4
is heterocyclyl, then heterocyclyl is bonded to the imidazo ring by an atom in heterocyclyl
that is other then nitrogen.
N-Q —
; R4 is alkyl, aryl, or heteroaryl; and R5 is
^(CH 2 ) a .
-m — otr\\ 1 1
-N-C(R 6 ) -N-S(0) 2
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For certain embodiments, R2 is selected from the group consisting of -R4, -X-Rj,
-X-Y-R4, and -X-R 5 .
For certain embodiments, including any one of the above embodiments wherein R2
is present, R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
5 and hydroxyalkylenyl. For certain embodiments, R 2 is selected from the group consisting
of hydrogen, alkyl, and alkoxyalkylenyl For certain embodiments, R2 is selected from the
group consisting of alkyl and alkoxyalkylenyl. For certain embodiments, R2 is selected
from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, ethoxymethyl,
methoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. For certain
10 embodiments, R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl,
ethoxymethyl, methoxymethyl, and 2-methoxyethyl.
For certain embodiments, R3 is selected from the group consisting of -Z-Y-R4,
-Z-Y-X-Y-R4, -Z-R 5 , -Z-Het, -Z-Het'-R*, and -Z-Hef-Y-R*
For certain embodiments, including any one of the above embodiments, R3 is
15 -Z-Y-R4 or -Z-Y-X-Y-R4. For certain of these embodiments, R3 is -Z-Y-R4. In
certain of these embodiments, Y is -N(Rs)-Q-, and R4 is alkyl, aryl, heteroaryl, or
heterocyclyl. In certain of these embodiments, Q is -C(R6)-, -S(0) 2 -, or -C(R6)-N(Rg)-.
For certain of these embodiments, Q is -C(R6)-. Alternatively, for certain of these
embodiments, Q is -S(0) 2 -. Alternatively, for certain of these embodiments, Q is -C(R6)-
20 N(Rg)-. Alternatively, for certain of these embodiments, Q is -C(R6)-0-. Alternatively,
for certain of these embodiments, Q is -S(0) 2 -N(R 8 )-. For certain of these embodiments
where R 3 is -Z-Y-R4 or -Z-Y-X-Y-R4, R 3 is -Z-Y-X-Y-R,.
In certain embodiments, including any one of the above embodiments wherein R3
is -Z- Y-R4 or -Z-Y-X-Y-R4, except where excluded, Y is -C(R 6 )-N(R 8 )-, and R4 is alkyl,
25 aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, or heterocyclyl. For certain of these
embodiments, Y in -Y-R4 is -C(R<s)-N(R8)-. For certain of these embodiments, R$ is =0,
Rs is Cm alkyl, and R4 is Cm alkyl. For certain of these embodiments, Cm alkyl is
methyl.
In certain embodiments, including any one of the above embodiments wherein R3
30 is -Z-Y-R4 or -Z-Y-X-Y-R4, except where excluded, -Y-R4 is -C(0>NH 2 .
In certain embodiments, including any one of the above embodiments wherein R3
is -Z-Y-X-Y-R4, except where excluded, Y in -Z-Y- is -C(O)-, and Y in -Y-R4 is selected
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PCT/US2006/004713
from the group consisting of -C(0)-NH-, -C(O)-, and -C(0)-O. For certain of these
embodiments, R4 is alkyl, and when Y in -Y-R4 is -C(0)-NH-, then R4 can also be
hydrogen. For certain of these embodiments, X is heterocyclylene or heterocyclylene-
alkylene.
5 In certain embodiments, including any one of the above embodiments wherein R 3
is -Z-Y-R4 or -Z-Y-X-Y-R4, except where excluded, Y is -C(0> and R4 is heterocyclyl.
In certain embodiments, including any one of the above embodiments wherein R3
is -Z-Y-R4, except where excluded, Y is -C(0>, and R4 is heterocyclyl which is
unsubstituted or substituted by one or more substituents independently selected from the
10 group consisting of alkyl, hydroxy, and oxo.
In certain embodiments, including any one of the above embodiments wherein R3
is -Z-Y-R4, except where excluded, Y is -C(0)-NH-, and R4 is heterocyclyl which is
unsubstituted or substituted by one or more substituents independently selected from the
group consisting of alkyl, hydroxy, and oxo, or R4 is alkyl which is unsubstituted or
15 substituted by one or more substituents independently selected from the group consisting
of hydroxy, alkoxy, heteroaryl, and heterocyclyl.
For certain embodiments, including any one of the above embodiments wherein R4
is heterocyclyl, heterocyclyl is selected from the group consisting of tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
20 1,1 -dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1 ,4-oxazepanyl, diazepanyl,
dihydroisoquinolin-(l#)-yl, octahydroisoquinolin-(l#)-yl, dihydroquinolin-(2//)-yl>
octahydroquinolin-(2/f)-yl, dihydro-liHmidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and
piperazinyl. For certain of these embodiments, heterocyclyl is pyrrolidinyl or piperidinyl.
Alternatively, for certain of these embodiments, heterocyclyl is 1,1-
25 dioxidotetrahydrothien-3-yl, or 2-oxopyrrolidin-l -yl.
In certain embodiments, including any one of the above embodiments wherein R3
is -Z-Y-R4, except where excluded, Y is selected from the group consisting of -C(0)-0-,
-S(0) 2 -, and -S(0)2-N(Rs)-. For certain of these embodiments, Y is -S(0) 2 -. For certain
of these embodiments, Y is -S(0) 2 -N(R 8 ). For certain of these embodiments, Y is
30 -C(0)-O. For certain of these embodiments, R4 is alkyl.
In certain embodiments, including any one of the above embodiments wherein R 3
is -Z-Y-R4, except where excluded, Y is -0-, and R4 is hydrogen.
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In certain embodiments, including any one of the above embodiments wherein R3
hydroxyalkyl.
For certain embodiments, including any one of the above embodiments not
excluding this definition, R3 is -Z-R5. In certain of these embodiments, R5 is
(CH 2 ) b -^ In certain 0 f these embodiments, V is -NH-C(O)- or -C(O)-; A is
-0-, -CH2-, -S-, or -SO2-; a is 1, 2, or 3; and b is 2.
For certain embodiments wherein R3 is -Z-R5, R5 is -C=N. In certain of these
embodiments, Z is other than a bond. In certain of these embodiments, Z is alkylene.
Alternatively, in certain of these embodiments, R3 is -CH=CH-C=N.
For certain embodiments, including any one of the above embodiments not
excluding this definition, R 3 is -Z-Het or -Z-Het'-Ri. In certain of these embodiments, Het
and Het* are, respectively, selected from the group consisting of the monovalent and
divalent forms of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl,
azepanyl, 1,4-oxazepanyl, diazepanyl, dihydroisoquinolin-(li:0-yl> octahydroisoquinolin-
(l#)-yl, dihydroquinolin-(2/2)-yl, octahydroquinolin-(2//)-yl> dihydro-l/f-imidazolyl, 3-
azabicyclo[3.2.2]non-3-yl, and piperazinyl, each of which is unsubstituted or substituted
by one or more substitutents. For certain of these embodiments, Het and Het' are,
respectively, selected from the group consisting of the monovalent and divalent forms of
pyrrolidinyl, piperidinyl, and morpholinyl, each of which is unsubstituted or substituted by
one or more substitutents. For certain of these embodiments, Het is unsubstituted. For
certain of these embodiments, Het f is unsubstituted. For certain of these embodiments, R4
is heterocyclyl. For certain of these embodiments, Het is substituted by one or more
substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl,
hydroxyalkyleneoxyalkylenyl, and dialkylamino.
For certain embodiments, including any one of the above embodiments, except
where excluded, Z is Cm alkylene or C2-4 alkenylene. For certain of these embodiments,
Z is C2-4 alkylene. For certain of these embodiments, Z is ethylene.
is -Z- Y-R4, except where excluded, Y is
— V-N
is -C(O)-, and R4 is
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For certain embodiments, including any one of the above embodiments not
excluded by the proviso for Formulas I through VI, and which does not exclude this
definition, Z is a bond.
For certain embodiments, including any one of the above embodiments, R 3 is at the
5 7-position.
For certain embodiments, R4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,
10 heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and
heterocyclyl groups can be unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,
arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino,
15 alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl,
alkynyl, and heterocyclyl, oxo.
For certain embodiments, R4 is selected from the group consisting of alkyl, aryl,
arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl;
wherein alkyl is unsubstituted or substituted by one or more substituents selected from the
20 group consisting of hydroxy, alkoxy, and aryl; wherein aryl and arylalkylenyl are
unsubstituted or substituted by one or more substituents selected from the group consisting
of alkyl, halogen, cyano, dialkylamino, and alkoxy; and wherein heterocyclyl is
unsubstituted or substituted by one or more alkyl substituents.
For certain embodiments, R4 is alkyl, aryl, arylalkylenyl, heteroaryl,
25 heteroarylalkylenyl, or heterocyclyl.
For certain embodiments, R4 is alkyl, aryl, heteroaryl, or heterocyclyl
For certain embodiments, R4 is alkyl, aryl, or heteroaryl.
For certain embodiments, R4 is alkyl substituted by heterocyclyl. For certain of
these embodiments, heterocyclyl is substituted by one or two oxo groups.
30 For certain embodiments, R4 is heterocyclyl.
For certain embodiments, R4 is hydrogen or alkyl.
For certain embodiments, R4 is alkyl.
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For certain embodiments, R4 is Cm alkyl.
For certain embodiments, R4 is methyl.
For certain embodiments, R4 is hydrogen.
For certain embodiments, R5 is selected from the group consisting of:
-N-C(Re) ~N-S(0) 2 _ v _^ > -f N-C(R 6 )-N A
-ON.
For certain embodiments, R5 is selected from the group consisting of:
-N-C(R 6 ) ~N-S(0) 2 _ v -^ \ -f N-C(R 6 )-N A
^(CH 2 )
-in— o V rx 6 ; - ~v~ /2 — v-N A -r- y ~v*e> r
and
-v-^ <CH ^ A
For certain embodiments, R 5 is ( CH 2)b
^(CH 2 ) a ^
2^b
-v-rf A
W^jVis-J
1 0 For certain embodiments, R 5 is ^"Jb-^ ; V is -NH-C(O)- or -C(0>; A
is -O, -CH 2 ~ 3 -S-, or -S0 2 -; a is 1, 2, or 3; and b is 2.
For certain embodiments, R5 is -C=N.
For certain embodiments, R6 is selected from the group consisting of =0 and =S.
For certain embodiments, R6 is =0.
1 5 For certain embodiments, R 7 is C2-7 alkylene.
For certain embodiments, R7 is C2-4 alkylene.
For certain embodiments, R 8 is selected from the group consisting of hydrogen,
alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl.
For certain embodiments, Rg is selected from the group consisting of hydrogen,
20 Cm alkyl, and C 1 -4 alkoxy C 1 -4 alky leny L
For certain embodiments, Rs is hydrogen or Cm alkyl.
For certain embodiments, Rs is Cm alkyl.
For certain embodiments, Rs is methyl.
For certain embodiments, Rs is hydrogen.
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For certain embodiments, R9 is selected from the group consisting of hydrogen and
alkyl.
For certain embodiments, Rio is C3-8 alkylene.
For certain embodiments, Rio is C4-6 alkylene.
5 For certain embodiments, Rio is C4.5 alkylene.
For certain embodiments, A is selected from the group consisting of -0-, -CH 2 -,
-C(O)-, -S(O) 0 -2-, and -NOR4)-.
For certain embodiments, A is -0-, -CH2-, -S-, or -S(0) 2 -.
For certain embodiments, A is -O- or -S(0>2-.
1 0 For certain embodiments, A is -S-.
For certain embodiments, A is -0-.
For certain embodiments, including any one of the above embodiments of Formula
VII, G is selected from the group consisting of-C(0)-R m , a-aminoacyl, a-aminoacyl-a-
aminoacyl, -C(0)-0~R m , -C(0)-N(R ,m )R m , -C(=NY,)-R"', -CH(OH)-C(0)-OY,,
1 5 -CH(OC M alkyl) Y 0 , -CH 2 Y 2 , and -CH(CH 3 )Y 2 . For certain of these embodiments, R m and
R ,IM are independently selected from the group consisting of Cmo alkyl, C3.7 cycloalkyl,
phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of halogen, hydroxy, nitro,
cyano, carboxy, C1-6 alkyl, Cm alkoxy, aryl, heteroaryl, aryl-Ci-4 alkylenyl,
20 heteroaryl-Ci.4 alkylenyl, halo-Ci-4 alkylenyl, halo-Ci-4 alkoxy, -0-C(0)-CH 3 ,
-C(0)-0-CH 3 , -C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 , with the proviso
that R ,m can also be hydrogen; a-aminoacyl is an a-aminoacyl group derived from an a-
amino acid selected from the group consisting of racemic, D-, and L-amino acids; Y\ is
selected from the group consisting of hydrogen, Cue alkyl, and benzyl; Y 0 is selected from
25 the group consisting of Cj^ alkyl, carboxy-Cj-6 alkylenyl, amino-Ci-4 alkylenyl,
mono-Ar-C]-6alkylamino-Ci_4 alkylenyl, and di-N,N-Ci- 6 alky lamino-C 1.4 alkylenyl; and
Y 2 is selected from the group consisting of mono-A^-Ci^ alkylamino,
di-A^iV-Ci.6alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, and
4-C 1 -4 alky lpiperazin- 1 -yl .
30 For certain embodiments, including any one of the above embodiments of Formula
VII, G is selected from the group consisting of -C(0)-R m , a-aminoacyl, and -C(0)-0-R m .
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For certain embodiments, including any one of the above embodiments of Formula
VII, G is selected from the group consisting of -C(0)-R m , a-amino-C2.11 acyl, and
-C(0)-0-R m . a-Amino-C 2 .i 1 acyl includes a-amino acids containing a total of at least 2
carbon atoms and a total of up to 1 1 carbon atoms, and may also include one or more
5 heteroatoms selected from the group consisting of O, S, and N. For certain of these
embodiments, R m contains one to ten carbon atoms.
For certain embodiments, including any one of the above embodiments which
include an a-aminoacyl group, a-aminoacyl is an a-aminoacyl group derived from a
naturally occuring a-amino acid selected from the group consisting of racemic, D-, and L-
10 amino acids.
For certain embodiments, including any one of the above embodiments which
include an a-aminoacyl group, a-aminoacyl is an a-aminoacyl group derived from an a-
amino acid found in proteins, wherein the the a-amino acid is selected from the group
consisting of racemic, D-, and L-amino acids.
15 In certain embodiments, Q is selected from the group consisting of a bond, -C(R6)-,
-C(R 6 )-C(R6)-, -S(0) 2 -, -C(R 6 )-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(R6)-0-, and -C(R6)-N(OR 9 )~.
In certain embodiments, Q is selected from the group consisting of -C(R6)-,
-C(R 6 )-C(R 6 )-, -S(0) 2 -, -C(R*)-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -CW-O-, and -C(R 6 )-N(OR 9 )-.
In certain embodiments, Q is other than a bond when R 3 is -Z- Y-R4 and Y is
20 -N(R«)-Q-.
In certain embodiments, Q is selected from the group consisting of a bond, -C(R6)-,
-SCO^and-C^-NCRjj)-.
In certain embodiments, Q
is -C(0)-NH-, -C(O)-, or -C(0)-0-.
In certain embodiments, Q
is -C(R 6 >.
In certain embodiments, Q
is -C(O)-.
In certain embodiments, Q
is -S(0) 2 -.
In certain embodiments, Q
is -C(R 6 )-N(R 8 >.
In certain embodiments, Q
is -C(0)-NH-.
In certain embodiments, Q
is -C(R 6 )-0-.
In certain embodiments, Q
is-SCO^NCR,)-.
In certain embodiments, Q
is a bond.
In certain embodiments, V
is selected from the group consisting of -C(R6)-,
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-0-C(R6>, -N(R 8 )-C(R*)-, and -S(0) 2 -.
In certain embodiments, V is selected from the group consisting of -C(O)- and
-NH-C(O)-.
In certain embodiments, W is selected from the group consisting of a bond, -C(O)-,
5 and -S(0) 2 -.
In certain embodiments, W is a bond or -C(O)-.
In certain embodiments, W is a bond.
In certain embodiments, X is selected from the group consisting of alkylene,
alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene,
10 alkenylene, and alkynylene groups can be optionally interrupted or terminated with
arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O-
groups.
In certain embodiments, X is alkylene.
In certain embodiments, X is heteroarylene-alkylene. For certain of these
1 5 embodiments, heteroarylene is thiazoldiyl.
In certain embodiments, X is heterocyclylene. For certain of these embodiments,
heterocyclylene is piperidin-l,4-diyl or piperazin-l,4-diyl.
In certain embodiments, Y is selected from the group consisting of -0-, -S(0)o_2->
-S(0) 2 -N(R8)-, -C(R6>, -C(R6)-0-, -O-C(R<0-, -0-C(0)-0-, -N(R 8 )-Q-, -C(R<)-N(R 8 )-,
-^f^N-Q — -N"C(R 6 ) y - W-
20 -0-C(R*)-N(R8)-, -C(R6)-N(OR 9 )-, Rl ° , R ?
-N— R 7 -N-Q-
-V-N V -f N-C(R e )-N
R 7 , Kl ° ,and Rl ° * . In certain of
these embodiments, including any one of the above embodiments wherein Y is present, Y
is other than -0-.
In certain embodiments, Y is -N(Rg)-C(0)-, -N(Rg)-S(0)2-, -N(R 8 )-C(0)-N(R 8 )-,
N-Q —
J
25 or Rl °
In certain embodiments, Y is -N(Rg)-Q-.
In certain embodiments, Y is -N(Rg)-Q-, and Q is -C(R<s)-, S(0) 2 -, or
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-C(R6>N(R 8 >.
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Y
In certain embodiments, Z
s-N(Rs)-C(R6)-.
s -NH-C(O)-.
s -NH-S(0) 2 -.
s -NH-C(0)-NH-.
s -NH-C(0)-0-.
s -NH-S(0) 2 -N(R 8 )-
s-C(R6)-N(R 8 >.
s -C(0)-NH-.
s -C(O)-.
is -C(0)-0-.
is -C(0)-NH-, -C(O)-, or -C(0)-0-.
is selected from the group consisting of a bond,
alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be
optionally interrupted with one or more -O- groups; with the proviso that Z is other than a
bond when:
R 3 is -Z- Y-R4 or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
-0-C(R6)-, -OC(0)-0, -0-C(R 6 )-N(R 8 )-,
— N-C(R 6 )-N-W-
10
-o-a&y
V
or
—V-N
Vr
— N— R 7 — N-Q—
R 7
wherein V is
N C7
or
R3 is -Z-R 5 , and R5 is
-N-C(R 6 ) — N— S(0) 2
,or
-v-i<r
\
(CH 2 ) a -^
A
(CH 2 ) b -^ wherein Vis
-0-C(R6)s or
R3 is -Z-Het, -Z-Het'-R4, or -Z-Het'-Y-R4, and Z is attached to a nitrogen
atom in Het or Her". In certain of these embodiments, Z is other than a bond
further when R5 is -C=N. In certain of these embodiments, Z is other than a bond
further when R 3 is -Z-Y-R4, Y is -C(O)- or -C(0)-0-, and R4 is alkyl.
In certain embodiments, Z is a bond except where excluded by the above proviso.
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In certain embodiments, Z is Cm alkylene or C2-4 alkenylene.
In certain embodiments, Z is C2-4 alkylene.
In certain embodiments, Z is ethylene.
In certain embodiments, Het is heterocyclyl which can be unsubstituted or
5 substituted by one or more substituents independently selected from the group consisting
of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano,
hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.
In certain embodiments, Het is selected from the group consisting of
tetraliydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl,
10 morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-
oxazepanyl, diazepanyl, dihydroisoquinolin-(l J £/)-yl, octahydroisoquinolin-(l#)-yl,
dihydroquinolin-(2//)-yl, octahydroquinolin-(2//)-yl, dihydro-l#-imidazolyl, 3-
azabicyclo[3.2.2]non-3-yl, and piperazinyl, each of which is unsubstituted or substituted
by one or more substitutents.
1 5 In certain embodiments, Het is substituted by one or more substituents selected
from the group consisting of alkyl, hydroxyl, hydroxyalkyl, hydroxyalkyleneoxyalkylenyl,
and dialkylamino.
In certain embodiments, Het is unsubstituted.
In certain embodiments, Het' is heterocyclylene which can be unsubstituted or
20 substituted by one or more substituents independently selected from the group consisting
of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano,
amino, alkylamino, dialkylamino, and oxo.
In certain embodiments, Het 1 is selected from the group consisting of the divalent
forms of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl,
25 morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-
oxazepanyl, diazepanyl, dihydroisoquinolin-(l//)-yl> octahydroisoquinolin-(l#)-yl,
dihydroquinolin-(2//)-yl, octahydroquinolin-(2#)-yl, dihydro-l//-imidazolyl, 3-
azabicyclo[3.2.2]non-3-yl, and piperazinyl, each of which is unsubstituted or substituted
by one or more substitutents.
30 In certain embodiments, Het' is unsubstituted (except by -R4 or -Y-R4).
In certain embodiments, a and b are independently integers from 1 to 6 with the
proviso that a + b is < 7.
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In certain embodiments, a and b are each independently 1 to 3.
In certain embodiments, a and b are each 2.
In certain embodiments, a is 1, 2, or 3, and b is 2.
In certain embodiments, n is 0 or L
In certain embodiments, n is 0.
Preparation of the Compounds
Compounds of the invention may be synthesized by synthetic routes that include
processes analogous to those well known in the chemical arts, particularly in light of the
description contained herein. The starting materials are generally available from
commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin, USA) or are
readily prepared using methods well known to those skilled in the art (e.g., prepared by
methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic
Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R. Katritsky, Otto Meth-
Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v. 1-
6, Pergamon Press, Oxford, England, (1995); Barry M. Trost and Ian Fleming,
Comprehensive Organic Synthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); or
Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin,
Germany, including supplements (also available via the Beilstein online database)).
For illustrative purposes, the reaction schemes depicted below provide potential
routes for synthesizing the compounds of the present invention as well as key
intermediates. For more detailed description of the individual reaction steps, see the
EXAMPLES section below. Those skilled in the art will appreciate that other synthetic
routes may be used to synthesize the compounds of the invention. Although specific
starting materials and reagents are depicted in the reaction schemes and discussed below,
other starting materials and reagents can be easily substituted to provide a variety of
derivatives and/or reaction conditions. In addition, many of the compounds prepared by
the methods described below can be further modified in light of this disclosure using
conventional methods well known to those skilled in the art.
In the preparation of compounds of the invention it may sometimes be necessary to
protect a particular functionality while reacting other functional groups on an intermediate.
The need for such protection will vary depending on the nature of the particular functional
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group and the conditions of the reaction step. Suitable amino protecting groups include
acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9-
fluorenylmethoxycarbonyl (Fmoc). Suitable hydroxy protecting groups include acetyl and
silyl groups such as the terr-butyl dimethylsilyl group. For a general description of
protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, John Wiley & Sons, New York, USA, 1991.
Conventional methods and techniques of separation and purification can be used to
isolate compounds of the invention, as well as various intermediates related thereto. Such
techniques may include, for example, all types of chromatography (high performance
liquid chromatography (HPLC), column chromatography using common absorbents such
as silica gel, and thin layer chromatography), recrystallization, and differential (i.e., liquid-
liquid) extraction techniques.
For some embodiments, compounds of the invention can be prepared according to
Reaction Scheme I, wherein Ri, R 2 , R, and n are as defined above; Hal is -Br or -I; R 3a is
selected from the group consisting of -C(H)=C(H)-Z a -Y-R4, -C(H)=C(H)-Z a -Y-X-Y-R4,
-C(H)=C(H)-Z a -R 5 , -C(H)=C(H)-Z a -Het, -C(H)=C(H)-Z a -Het , -R 4 ,
«C(H)=C(H)-Z a -Het'-Y-R4, -N(R 8 )-C(R*)-R4, -N(R 8 )-S0 2 -R4, and
^(CH 2 ) a ^
~N(R 8 )-C(R 6 )-N A
(CH 2 ) b ^ ^ w herein R 8 , R^, R 5 , R4, Y, X, Het, and Hef are as defined
above, and Z a is selected from the group consisting of a bond and alkylene, wherein
alkylene can be optionally interrupted with one or more -O- groups; and R 3b is selected
from the group consisting of -CH 2 -CH 2 -Z a -Y-R4, -CH 2 -CH 2 -Z a -Y-X-Y-R4,
-CH 2 -CH 2 -Z a -R 5 , -CH 2 -CH 2 -Z a -Het, -CH 2 -CH 2 -Z a -Het'-R4, and -CH 2 -CH 2 -Z a -Het'-Y-R4,
wherein R 5 , R4, Z a , Y, X, Het, and Het' are as defined above. Numerous compounds of
Formula XV are known; see, for example, U.S. Patent Application Publication No. US
2004/0147543 and the documents cited therein.
The Heck reaction is used in step (1) of Reaction Scheme I to provide compounds
of Formula Ha, wherein R 3a is selected from the group consisting of -C(H)=C(H)-Z a -Y-R4,
-C(H)=C(H)-Z a -Y-X-Y-R4, -C(H)=C(H)-Z a -R 5 , -C(H)=C(H)-Z a -Het,
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-C(H)=C(H>Z a -Het'-R4, and -C(H)=C(H)-Z a -Het'-Y-R4. The Heck reaction is carried out
by coupling a l#-imidazo[4,5-c]qiunolin-4-amine of Formula XV with a compound of the
Formula H 2 C=C(H)-Z a ~Y-R4, H 2 C=C(H)-Za-Y-X-Y-R4, H 2 C=C(H)-Z a ~R 5 ,
H 2 C=C(H)-Z a -Het, H 2 0=C(H)-Z B -Het , -R 4 , or H 2 C=C(H)-Z a -Het , -Y-R 4 . Several of these
5 vinyl-substituted compounds are commercially available; others can be prepared by
known methods. For example, vinyl-substituted compounds are readily prepared from
aldehydes, primary alcohols, or primary alkyl halides using a variety of conventional
methods. The reaction is conveniently carried out by combining the compound of
Formula XV and the vinyl-substituted compound in the presence of palladium (II) acetate,
1 0 triphenylphosphine or tri-or/Zzo-tolylphosphine, and a base such as triethylamine or cesium
carbonate in a suitable solvent such as acetonitrile, toluene, or N, JV-dimethylformamide
(DMF). The reaction can be carried out at an elevated temperature such as 85 °C to 125
°C under an inert atmosphere. The product of Formula Ha, a subgenus of Formulas I and
II, or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
1 5 The Heck reaction can also be carried out on a trifluoromethanesulfonate-substituted lif-
imidazo[4,5-c]quinolin-4-amine, in which Hal in Formula XV is replaced by -0(SO) 2 -CF3.
It is understood by one skilled in the art that certain substrates are not compatible with
Heck reaction chemistry; see, R. F. Heck, in Comprehensive Organic Synthesis, Vol. 4
(Eds.: B. M. Trost, I. Fleming), Pergamon Press, Oxford, p. 833, (1991). For example, it
20 is understood by one skilled in the art that for the Heck reaction described above, Z a is
other than a bond when a Y group bonded to Z a is -0-, -0-C(R6)-, -OC(0)-0-,
-0-C(R6)-N(Rs)-, Rl ° wherein V is -O-CCRe)-, or R ? ;or
A
when the R 5 bonded to Z a is ( CH 2)b-' / wherein V is -0-C(R 6 )-; or when Z a is
attached to a nitrogen atom in Het or Hef.
25 A copper-mediated coupling reaction can be used to prepare compounds of
Formula Ha, wherein R 3a is -N(R8)-C(R6)-R4, -N(R 8 )-S0 2 -R4, or
41
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10
15
20
^(CH 2 ) a ^
-N(R 8 )-C(R 6 )-N A
(CH 2 )„— ^ jj^g reac tj on j s conveniently carried out by combining the
l/Wmidazo[4,5-c]quinolin-4-amine of the Formula XV and an amide, sulfonamide, or
HN(R 8 )-C(R 6 )-N A
V
urea of formula HN(R 8 )-Q-R4 or ( CH 2 )b-^ i n the presence of copper (I)
iodide, potassium phosphate, and racemic rra/w-l,2-diaminocyclohexane in a suitable
solvent such as 1,4-dioxane. The reaction can be carried out at an elevated temperature
such as 1 10 °C. Many amides, sulfonamides, and ureas are commercially available; others
can be made by conventional methods. The compound or a pharmaceutical^ acceptable
salt thereof can be isolated using conventional methods.
The compounds of Formula Ha prepared by the Heck reaction, can undergo
reduction of the alkenylene group present in step (2) of Reaction Scheme I to provide
compounds of Formula lib. The reduction can be carried out by hydrogenation using a
conventional heterogeneous hydrogenation catalyst such as palladium on carbon. The
reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as
ethanol, methanol, or mixtures thereof. The product of Formula lib, a subgenus of
Formulas I and II, or a pharmaceutical^ acceptable salt thereof can be isolated using
conventional methods.
Reaction Scheme I
NH,
25
For some embodiments, compounds of the invention can be prepared according to
Reaction Scheme II, wherein Ri, R2, R3a> R3b, R, Hal, and n are as defined above. In steps
(1) and (2) of Reaction Scheme II, a l//-imidazo[4,5-c]quinoline of Formula XVI
undergoes a metal-mediated coupling reaction to provide a compound of Formula Xa,
which may be reduced in step (2) to a compound of Formula Xb. Compounds of Formula
Xa and Xb are subgenera of Formula X. Steps (1) and (2) of Reaction Scheme II can be
carried out according to the methods described in steps (1) and (2) of Reaction Scheme I.
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Numerous compounds of Formula XVI are known; see, for example, U.S. Patent
Publication Application No. US 2004/0147543 and the documents cited therein.
In steps (3a) and (3b) of Reaction Scheme II, l//-imidazo[4,5-c]quinolines of
Formula Xa and Xb are oxidized to provide l#-imidazo[4,5-c]quinoline-5N-oxides of
5 Formulas XVII and XVIII, respectively, using a conventional oxidizing agent capable of
forming N-oxides. The reaction is conveniently carried out by adding 3-
chloroperoxybenzoic acid at room temperature to a solution of a compound of Formula Xa
or Xb in a solvent such dichloromethane or chloroform. Alternatively, the oxidation can
be carried out by heating a solution of a compound of Formula Xa or Xb in a suitable
1 0 solvent such as ethyl acetate with peracetic acid at a temperature such as 50 °C and then
adding sodium metabisulfite.
In steps (4a) and (4b) of Reaction Scheme II, l#-imidazo[4,5-c]quinoline-5N-
oxides of Formulas XVII and XVIII are aminated to provide l#~imidazo[4,5-c]quinolin-4-
amines of Formulas Ha and lib, respectively. The animation can be carried out by the
1 5 activation of an N-oxide of Formula XVII or XVIII by conversion to an ester and then
reacting the ester with an aminating agent. Suitable activating agents include alkyl- or
arylsulfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, or p-
toluenesulfonyl chloride. Suitable aminating agents include ammonia, in the form of
ammonium hydroxide, for example, and ammonium salts such as ammonium carbonate,
20 ammonium bicarbonate, and ammonium phosphate. The reaction is conveniently carried
out by adding ammonium hydroxide followed by /?-toluenesulfonyl chloride to a solution
of the TV-oxide of Formula XVII or XVIII in a suitable solvent such as chloroform or
dichloromethane at room temperature. The reaction may also be carried out by adding
ammonium hydroxide and /?-toluenesulfonyl chloride to the reaction mixture from step
25 (3a) or (3b) without isolating the TV-oxide of Formula XVII or XVIII. The product or a
pharmaceutical^ acceptable salt thereof can be isolated using conventional methods.
Alternatively step (4a) or (4b) can be carried out by the reaction of a IH-
imidazo[4,5-c]quinoline-5N-oxide of Formula XVII or XVIII with trichloroacetyl
isocyanate followed by hydrolysis of the resulting intermediate to provide a compound of
30 Formula Ha or lib. The reaction is conveniently carried out in two steps by (i) adding
trichloroacetyl isocyanate to a solution of the N-oxide of Formula XVII or XVIII in a
solvent such as dichloromethane and stirring at room temperature to provide an isolable
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amide intermediate. In step (ii), a solution of the intermediate in methanol is treated with
a base such as sodium methoxide or ammonium hydroxide at ambient temperature. The
product or a pharmaceutically acceptable salt thereof can be isolated using conventional
methods.
An R 3a or R 3b group in a compound of Formula Xa or Xb may contain a -S-
functional group, which can be oxidized to -S(0)2- in step (3 a) or (3b) of Reaction Scheme
II using an excess of the oxidizing agent. Step (4a) or (4b) of Reaction Scheme II may
then be carried out to provide a compound of Formula Ha or lib, wherein R3 a or R 3b
contains a -S(0)2- functional group.
Reaction Scheme II
FL, Ma R 3b lib
For some embodiments, compounds of the invention can be prepared according to
Reaction Scheme III, wherein Ri, R 2 , R4, Rs, A, R, Z a , Hal, a, b, and n are as defined
above. In step (1) of Reaction Scheme III, a l//-imidazo[4,5-c]quinolin-4-amine of
Formula XV is coupled with an ester of formula H 2 C=C(H)-C(0)-OaIkyl to provide an
ester-substituted li/-imidazo[4,5-c]quinolin-4-amine of Formula XIX, a subgenus of
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Formulas I and II. The reaction can be carried out under the Heck reaction conditions
described in step (1) of Reaction Scheme I. Some esters of formula
H 2 C=C(H)-C(0)-0-alkyl, for example methyl acrylate, are commercially available; others
can be prepared by known methods. The conditions described in step (2) of Reaction
5 Scheme I may then be used to reduce the double bond in a compound of Formula XIX in
step (2) of Reaction Scheme III to provide an ester-substituted l#-imidazo[4,5-c]quinolin-
4-amine of Formula XX, a subgenus of Formulas I and II.
In step (3) of Reaction Scheme III, the ester group of a li/-imidazo[4,5-c]quinolin-
4-amine of Formula XX undergoes base-promoted hydrolysis to the carboxylic acid of
10 Formula XXI. The hydrolysis reaction is conveniently carried out by combining a
compound of Formula XX with a base such as potassium hydroxide or sodium hydroxide
in a suitable solvent mixture such as an alcohol/water mixture, preferably a
methanol/water mixture. The reaction can be carried out at room temperature, and the
product of Formula XXI, a subgenus of Formulas I and II, or a pharmaceutical^
15 acceptable salt thereof can be isolated by conventional methods.
A carboxylic acid of Formula XXI is converted into an amide of Formula Ilg or Ilh
in step (4) or (4a) of Reaction Scheme III using conventional methods. The reaction is
conveniently carried out by treating a solution of a carboxylic acid of Formula XXI with a
secondary amine of formula HN(Rg)R4 or
^(CH 2 ) a ^
HN A
20 V (CH 2 ) b — md a C0U pii n g a gent, such as 1 -[3-(dimethylamino)propyl-3-
ethylcarbodiimide hydrochloride, in the presence of 1-hydroxybenzotriazole. The reaction
can be carried out at room temperature in a suitable solvent such as DMF, and the product
of Formula Ilg or Ilh, which are subgenera of Formulas I and II, or a pharmaceutical^
acceptable salt thereof, can be isolated by conventional methods. Numerous secondary
25 amines are commercially available; others can be prepared by known synthetic methods.
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10
Reaction Scheme III
NH,
N'
f NH2 (CH 2 ) a
(CH 2 ) b )
-A y
For some embodiments, compounds of the invention can be prepared according to
Reaction Scheme IV, wherein Rj, R2, Rt, Rs, Q, R, Z a , Hal, and n are as defined above;
O
-N S(0) 2
-N C(O)
,or
\
(CH 2 ) a -^
A
■N V
s V (CH 2 ) b
> 8
, wherein A, a, b, R7,
and Rsa is
and Rg are as defined above.
In step (1) of Reaction Scheme IV, a lif-imidazo^^S-^quinoline of Formula XVI
undergoes a Heck coupling reaction, according to the method described in step (1) of
Reaction Scheme I, with an alkenyl-substituted phthalimide of formula
O
^ N a
0 , which is commercially available or can be prepared by known
methods. The resulting compound of Formula XXIII may then be reduced in step (2)
according to the method described in step (2) of Reaction Scheme I. Compounds of
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Formula XXIII and XXIV are subgenera of Formula X and can be isolated by
conventional methods.
In steps (3) and (4) of Reaction Scheme IV, a phthalimide-substituted 177-
imidazo[4,5-c]quinoline of Formula XXIV is first oxidized to a 5iV-oxide of Formula
5 XXV, which is then aminated to provide a phthalimide-substituted l#-imidazo[4,5-
c]quinolin-4-amine of Formula XXVI, a subgenus of Formulas I and EL Steps (3) and (4)
of Reaction Scheme IV can be carried out according to the methods described in steps (3 a)
and (4a) of Reaction Scheme II, and the product or a pharmaceutical^ acceptable salt
thereof can be isolated by conventional methods.
10 In step (5) of Reaction Scheme IV, the phthalimide group of a l//-imidazo[4,5-
c]quinolin-4-amine of Formula XXVI is removed to provide an amino-substituted 1/f-
imidazo[4,5-c]quinolin-4-amine of Formula XXVII, a subgenus of Formulas I and EL The
reaction is conveniently carried out by adding hydrazine or hydrazine hydrate to a solution
or suspension of a compound of Formula XXVI in a suitable solvent such as ethanol. The
1 5 reaction can be carried out at room temperature or at an elevated temperature, such as the
reflux temperature of the solvent. The product or a pharmaceutical^ acceptable salt
thereof can be isolated by conventional methods.
In step (6) or (6a) of Reaction Scheme IV, an amino-substituted l//-imidazo[4,5-
c]quinolin-4-amine of Formula XXVII is converted to a l//-imidazo[4,5-c]quinolinyl
20 compound of Formula XXVIII or XXIX, subgenera of Formulas I and II, using
conventional methods. For example, an amino-substituted ltf-imidazo[4,5-c]quinolin-4-
amine of Formula XXVII can react with an acid chloride of Formula R4C(0)C1 to provide
a compound of Formula XXVIII in which -QR4 is -C(0>R4. In addition, a IH-
imidazo[4,5-c]quinolin-4-amine of Formula XXVII can react with sulfonyl chloride of
25 Formula R4S(0)2C1 or a sulfonic anhydride of Formula (R4S(0) 2 )20 to provide a
compound of Formula XXVIII in which -QR4 is -S(0) 2 -R4. Numerous acid chlorides of
Formula R4C(0)C1 5 sulfonyl chlorides of Formula R4S(0) 2 C1, and sulfonic anhydrides of
Formula (R4S(0) 2 ) 2 0 are commercially available; others can be readily prepared using
known synthetic methods. The reaction is conveniently carried out by adding the acid
30 chloride of Formula R4C(0)C1, sulfonyl chloride of Formula R4S(0) 2 C1, or sulfonic
anhydride of Formula (I^O^O to a solution of the amino-substituted l#-imidazo[4,5-
c]quinolin-4-amine of Formula XXVII in a suitable solvent such as chloroform,
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dichloromethane, or l-methyl-2-pyrrolidinone. Optionally a base such as triethylamine,
pyridine, or A/;N-diisopropylethylamine, or a combination thereof can be added. The
reaction can be carried out at room temperature or initially at a sub-ambient temperature
such as 0 °C and then warming to room temperature. The product or a pharmaceutically
5 acceptable salt thereof can be isolated using conventional methods.
N — S(0) 2 N — C(O)
V * V >
R R
Compounds of Formula XXIX where Rs a is 7 or 7
can be prepared by treating an amino-substituted l//-imidazo[4,5-c]quinolin-4-amine of
Formula XXVII with a chloroalkanesulfonyl chloride of Formula C1-R 7 S(0)2C1 or a
chloroalkanoyl chloride of Formula C1-R.7C(0)C1. The reaction is conveniently carried
10 out by adding the chloroalkanesulfonyl chloride or chloroalkanoyl chloride to a solution of
the amino-substituted liWmidazo[4,5-c]quinolin-4-amine of Formula XXVII in a suitable
solvent such as chloroform at ambient temperature. The isolable intermediate
chloroalkanesulfonamide or chloroalkanamide can then be treated with a base such as 1,8-
diazabicyclo[5.4.0]undec-7-ene in a suitable solvent such as DMF to effect the cyclization.
1 5 The product or a pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
Ureas of Formula XXVIII, where -QR4 is -C(R6)-NH-W-R4, Rsis =0, and W is a
bond, can be prepared by reacting an amino-substituted l/f-imidazo[4,5-c]quinolin-4-
amine of Formula XXVII with isocyanates of Formula R4N=C=0. Numerous isocyanates
20 of Formula R4N=C=0 are commercially available; others can be readily prepared using
known synthetic methods. The reaction can be conveniently carried out by adding the
isocyanate of Formula R4N=C=0 to a solution of the amino-substituted lif-imidazo[4,5-
c]quinolin-4-amine of Formula XXVII in a suitable solvent such as dichloromethane or
chloroform. Optionally a base such as triethylamine can be added. The reaction can be
25 carried out at room temperature or initially at a sub-ambient temperature such as 0 °C and
then warming to room temperature. Alternatively, a compound of Formula XXVII can be
treated with an isocyanate of Formula R4(CO)N=C=0, a thioisocyanate of Formula
R4N=C=S, a sulfonyl isocyanate of Formula R4S(0)2N=C=0, or a carbamoyl chloride of
CI \^
Formula R4N-(R 8 )-C(0)C1, or ( CH 2 )b to provide a compound of Formula
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XXVIII, wherein -QR4 is -C(R 6 )-N(R 8 )-W-, where Re, Rs, and W are as defined above, or
pharmaceutical^ acceptable salt thereof can be isolated using conventional methods.
Sulfamides of Formula XXVIII, where -QR4 is -S(0) 2 -N(R8)-R4 can be prepared
by reacting a compound of Formula XXVII with sulfuryl chloride to generate a sulfamoyl
chloride in situ, and then reacting the sulfamoyl chloride with an amine of formula
HN(R 8 )R4. Alternatively, sulfamides of Formula XXVIII can be prepared by reacting a
compound of Formula XXVII with a sulfamoyl chloride of formula R4(R8)N-S(0) 2 C1.
The product or a pharmaceutical^ acceptable salt thereof can be isolated using
conventional methods. Many amines of Formula HN(Rg)R4 and some sulfamoyl chlorides
of formula R4(R 8 )N-S(0)2C1 are commercially available; others can be prepared using
known synthetic methods.
Compounds of Formula XXVIII, wherein Rg is other than hydrogen can be
prepared by reductive alkylation of the amino-substituted l//-imidazo[4,5-c]quinolin-4-
amine of Formula XXVII. The alkylation is conveniently carried out in two parts by (i)
adding an aldehyde or ketone to a solution of an amino-substituted l//-imidazo[4,5-
c]quinolin-4-amine of Formula XXVII or a salt thereof in a suitable solvent such as DMF
in the presence of a base such as iV^diisopropylethylamine. In part (ii) the reduction is
carried out by adding a suitable reducing agent such as the borane-pyridine complex. Both
part (i) and part (ii) can be carried out at ambient temperature, and the product or a
pharmaceutically acceptable salt thereof can be isolated using conventional methods. The
resulting compound can undergo reaction with an acid chloride, sulfonyl chloride, sulfonic
anhydride, isocyanate, or carbamoyl chloride as described above to provide a compound
of Formula XXVIII, wherein R 8 is other than hydrogen.
a compound of Formula XXIX wherein is
'8
. The product or a
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Reaction Scheme IV
For some embodiments, compounds of the invention can be prepared according to
Reaction Scheme V, wherein R u R 2 , Z a , R, and ri are as defined above; LG is a leaving
5 group such as -CI, -Br, -I, -0(SO) 2 CH 35 or -0(SO) 2 CF 3 ; R 3c is -Zb-Y-R* -Zb-Y-X-Y-R*
-Z b -Rs, -Zb-Het, -Z b -Het f -R4, and -Z b -Het'-Y-R4, wherein Z b is selected from the group
consisting of alkylene, alkenylene, and alkynylene interrupted with one or more -O-
groups, and X, Y, R*, R 5 , Het, and Hef are as defined above; and R 3d is -Het, -Het'-Ri,
-Hef-Y-R* -S-R4, -S(0) 2 -R4, or
— N— R 7 -^I-Q~R 4
1 0 Ry , wherein Y, R4, R 7 , Q, Het, and Het' are as defined above.
In step (1) of Reaction Scheme V, an ester-substituted compound of Formula XX
is reduced to a hydroxyalkyl-substituted l#-imidazo[4,5-c]quinolin-4-amine of Formula
XXX using conventional methods. For example, the reduction may be carried out at room
temperature with lithium borohydride in a suitable solvent such as THF. The product or a
1 5 pharmaceutical^ acceptable salt thereof can be isolated by conventional methods.
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In step (2a) of Reaction Scheme V, a hydroxy-substituted compound of Formula
XXX is converted to an ether substituted l/f-imidazo[4,5~c]quinolin-4-amine of Formula
XXXI, which is a subgenus of Formulas I and II, using a Williamson-type ether synthesis.
The reaction is effected by treating a compound of Formula XXX with a halide of Formula
5 Halide-R 3c in the presence of a base. The reaction can be carried out by combining the
halide with a compound of Formula XXX in a suitable solvent such as DMF in the
presence of a base such as cesium carbonate. The reaction can be carried out at ambient
temperature or at an elevated temperature, for example, 60 to 85 °C. Alternatively, the
reaction can be carried out by treating a solution of a compound of Formula XXX in a
10 suitable solvent such as DMF with sodium hydride and then adding the halide.
In step (2) of Reaction Scheme V, a hydroxy-substituted compound of Formula
XXX is converted to a leaving group in a compound of Formula XXXII using a variety of
conventional methods. For example, a hydroxy-substituted compound of Formula XXX
can be chlorinated to provide a compound of Formula XXXII wherein LG is -CL
15 Conventional chlorinating reagents can be used. The reaction is conveniently carried out
by combining a compound of Formula XXX with thionyl chloride in a suitable solvent
such as dichloromethane and heating. Alternatively, the reaction may be run neat. A
hydroxy-substituted compound of Formula XXX can also be treated with methanesulfonic
anhydride to provide a compound of Formula XXXII wherein LG is -0(SO)2CH 3 .
20 In step (3) of Reaction Scheme V, the chloro group on a compound of Formula
XXXII can be displaced by a thiol under basic conditions to provide a compound of
Formula XXXIII wherein R 3 d is -S-R4. The reaction is conveniently carried out by adding
a thiol to a solution of a compound of Formula XXXII in the presence of a base such as
potassium tert-butoxide in a suitable solvent such as DMF. The product or a
25 pharmaceutical^ acceptable salt thereof can be isolated by conventional methods. A
compound of Formula XXXIII where R3d is -S-R4 can then be oxidized to a compound of
Formula XXXIII where R 3 d is -S(0)2-R4 using conventional oxidizing agents. The
reaction is conveniently carried out by adding peracetic acid to the compound of Formula
XXXIII where R 3 a is -S-R4 in a suitable solvent. The conversion of a compound of
30 Formula XXXII to a compound of Formula XXXIII where R 3d is -S(0) 2 -R4 can
conveniently be carried out in one pot without isolating the thioether from the reaction
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10
mixture. The product or a pharmaceutical^ acceptable salt thereof can be isolated by
conventional methods.
The chloro group on a compound of Formula XXXII can also be displaced by an
H-N— R 7 -N-Q-R 4
amine of Formula ^ 9 several of which are commercially available.
Other amines of this formula can be prepared by conventional methods. The reaction is
conveniently carried out by combining a compound of Formula XXXII with the amine in
the presence of a base such as potassium carbonate and in a suitable solvent such as DMF.
Catalytic sodium iodide can optionally be added. The reaction can be carried out at an
elevated temperature such as 50 °C or 90-100 °C, and the product can be isolated by
conventional methods. These reaction conditions can also be used employing a variety of
cyclic secondary amines, such as substituted or unsubstituted pyrrolidines, piperidines, or
morpholines, to provide compounds of Formula XXXIII wherein R.3d is -Het, -Het'-ILj, or
-Het'-Y-R4, wherein Het or Het 1 is attached to the -CH2- group at a nitrogen atom.
Reaction Scheme V
15
XXXIII
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For some embodiments, compounds of the invention can be prepared according to
Reaction Scheme VI wherein R\, R 2 , R3 a , R3t>, R, Hal, and n are as defined above. In step
(1) of Reaction Scheme VI, an aminopyridine of Formula XXXIV is treated with the
condensation product generated from 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's
5 acid) and triethyl orthoformate to provide an imine of Formula XXXV. The reaction is
conveniently carried out by adding a solution of an aminopyridine of Formula XXXIV to a
heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an
elevated temperature such as 70 °C.
In step (2) of Reaction Scheme VI, an imine of Formula XXXV undergoes
10 thermolysis and cyclization to provide a [l,5]naphthyridin-4-ol of Formula XXXVI. The
reaction is conveniently carried out in a medium such as DOWTHERM A heat transfer
fluid at a temperature in the range of 200 to 250 °C.
In step (3) of Reaction Scheme VI, the [l,5]naphthyridin-4-ol of Formula XXXVI
is nitrated under conventional nitration conditions to provide a 3-nitro[l,5]naphthyridin-4-
15 ol of Formula XXXVII. The reaction is conveniently carried out by heating the
[l,5]naphthyridin-4-ol of Formula XXXVI in nitric acid at an elevated temperature such as
90 °C
In step (4) of Reaction Scheme VI, a 3~nitro[l,5]naphthyridin-4~ol of Formula
XXXVII is chlorinated using conventional chlorination chemistry to provide a 4-chloro-3-
20 nitro[l,5]naphthyridine of Formula XXXVIII. The reaction is conveniently carried out by
treating the 3-nitro[l,5]naphthyridin-4-ol of Formula XXXVII with phosphorous
oxychloride in a suitable solvent such as DMF. The reaction can be carried out at ambient
temperature or at an elevated temperature such as 100 °C.
In step (5) of Reaction Scheme VI, a 4-chloro-3-nitro[l,5]naphthyridine of
25 Formula XXXVIII is treated with an amine of Formula Ri-NH 2 to provide a 3-
nitro[l,5]naphthyridin-4-amine of Formula XXXIX. Several amines of Formula Rj-NH 2
are commercially available; others can be prepared by known synthetic methods. The
reaction is conveniently carried out by adding the amine of Formula Ri-NH 2 to a solution
of the 4-chloro-3-nitro[l ,5]naphthyridine of Formula XXXIX in a suitable solvent such as
30 dichloromethane or methanol in the presence of a tertiary amine such as triethylamine.
The reaction can be carried out at ambient temperature or at a sub-ambient temperature
such as, for example, 0 °C.
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In step (6) of Reaction Scheme VI, a 3-nitxo[l,5]naphthyridin-4-amine of Formula
XXXIX is reduced to provide a [l,5]naphthyridine-3,4-diamine of Formula XL. The
reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst
such as platinum on carbon. The hydrogenation is conveniently carried out in a Parr
5 apparatus in a suitable solvent such as toluene, methanol, or acetonitrile. The reaction can
be carried out at ambient temperature.
Alternatively, the reduction in step (6) can be carried out using a one- or two-phase
sodium dithionite reduction. The reaction is conveniently carried out using the conditions
described by Park, K. K.; Oh, C. H.; and Joung, W. K.; Tetrahedron Lett, 34, pp. 7445-
10 7446 (1993) by adding sodium dithionite to a compound of Formula XXXIX in a mixture
of dichloromethane and water at ambient temperature in the presence of potassium
carbonate and ethyl viologen dibromide, ethyl viologen diiodide, or l,r~dwz-octyl-4,4-
bipyridinium dibromide.
In step (7) of Reaction Scheme VI, a [l,5]naphthyridine-3,4-diamine of Formula
15 XL is treated with a carboxylic acid equivalent to provide a l/f~imidazo[4,5-
c][l,5]naphthyridine of Formula XLI. Suitable carboxylic acid equivalents include
orthoesters of Formula R 2 C(0-alkyl) 3 , 1 , 1 -dialkoxyalkyl alkanoates of Formula
R 2 C(0-alkyl) 2 (0-C(0)-alkyl), and acid chlorides of Formula R 2 C(0)C1. The selection of
the carboxylic acid equivalent is determined by the desired substituent at R 2 . For example,
20 triethyl orthoformate will provide a compound where R 2 is hydrogen, and trimethyl
orthovalerate will provide a compound where R 2 is a butyl group. The reaction is
conveniently carried out by adding the carboxylic acid equivalent to a [l,5]naphthyridine-
3,4-diamine of Formula XL in a suitable solvent such as toluene or xylenes. Optionally,
catalytic pyridine hydrochloride can be added. The reaction is carried out at a temperature
25 high enough to drive off alcohol or water formed during the reaction. Conveniently, a
Dean-Stark trap can be used to collect the volatiles.
Alternatively, step (7) can be carried out in two steps when an acid chloride of
Formula R 2 C(0)C1 is used as the carboxylic acid equivalent. Part (i) of step (7) is
conveniently carried out by adding the acid chloride to a solution of a [l,5]naphthyridine-
30 3,4-diamine of Formula XL in a suitable solvent such as dichloromethane or acetonitrile to
afford an amide. Optionally, a tertiary amine such as triethylamine, pyridine, or 4-
dimethylaminopyridine can be added. The reaction can be carried out at room
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temperature. The amide product can be isolated and optionally purified using
conventional techniques. Part (ii) of step (7) involves heating the amide prepared in part
(i) to provide a l//-imidazo[4,5-c][l,5]naphthyridine of Formula XLI. The reaction is
conveniently carried out in a suitable solvent such as toluene at a temperature sufficient to
5 drive off water formed during the reaction. The reaction can also be carried out in a
solvent such as ethanol or methanol in the presence of a base such as triethylamine.
In steps (8) and (9) of Reaction Scheme VI, a l//-imidazo[4 3 5-c][l,5]naphthyridine
of Formula XLI is first oxidized to a 5JV-oxide of Formula XLII, which is then aminated to
provide a l//-imidazo[4 ? 5-c][l,5]naphthyridin-4-amine of Formula XLIII. Steps (8) and
1 0 (9) of Reaction Scheme VI can be carried out according to the methods described in steps
(3a) and (4a) of Reaction Scheme II.
In step (10) of Reaction Scheme VI a l//-imidazo[4,5-c][l,5]naphthyridin-4-amine
of Formula XLIII undergoes a metal-mediated coupling reaction to provide a compound of
Formula Ilia, which may be reduced, when appropriate, in step (1 1) to a compound of
15 Formula Illb. Compounds of Formula Ilia and Illb are subgenera of Formula IIL Steps
(10) and (1 1) of Reaction Scheme VI can be carried out according to the methods
described in steps (1) and (2) of Reaction Scheme I, and the products or pharmaceutically
acceptable salts thereof can be isolated by conventional methods.
Isomers of the compound of Formula XXXIV or Formula XXXVI can also be
20 synthesized and can be used to prepare compounds of Formulas IV, V, and VI according
to the methods shown in Reaction Scheme VL
For some embodiments, compounds in Reaction Scheme VI can be further
elaborated using conventional synthetic methods. For example, an amine of Formula
R1-NH2 may be substituted by a hydroxy or second amino group, which may be further
25 functionalized before step (7) of Reaction Scheme VI. Several examples of synthetic
elaborations of an Ri group on an imidazo ring compound are known. See, for example,
U.S. Patent Publication Application No. US 2004/0147543 and the documents cited
therein.
Similar synthetic transformations can be made at R 2 if, for example, the acid
30 chloride used in step (7) of Reaction Scheme VI contains a protected hydroxy or amino
group. Several acid chlorides of this type, for example acetoxyacetyl chloride, are
commercially available. Others can be prepared by known synthetic methods. For
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examples of synthetic elaborations of an R 2 group on an imidazo ring compound, see U.S.
Patent No. 5,389,640 (Gerster et al.).
Reaction Scheme VI
In some embodiments, compounds of the invention can be prepared according to
Reaction Scheme VII, wherein R, Ri, R 2 , R4, Rg> Q, Hal, and n are as described above.
In step (1) of Reaction Scheme VII, the Heck reaction is used to couple a halogen
substituted l#-imidazo[4,5-c]quinoline of Formula XV with acrylonitrile to provide a IH-
imidazo[4,5-c]quinoline of Formula XLIV. The reaction can be carried out as described in
step (1) of Reaction Scheme I.
In step (2) of Reaction Scheme VII, both the nitrile and the alkenylene groups in a
l#-imidazo[4,5-c]quinoline of Formula XLIV are reduced to provide an aminoalkyl
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10
15
20
substituted l#~imidazo[4,5-c]quinoline of Formula XLV. The reduction can be carried
out by hydrogenation using a conventional heterogeneous hydrogenation catalyst such as
palladium on carbon. The reaction can be carried out on a Parr apparatus in a suitable
solvent mix, such as methanol and trifluoroacetic acid.
In step (3) of Reaction Scheme VII, the amino group of a li/-imidazo[4,5-
c]quinoline of Formula XLV is further elaborated using the methods described in step (6)
of Reaction Scheme IV to provide a l//-imidazo[4,5-c]quinoline of Formula XLVI, which
is a subgenus of Formulas I and II. The product or a pharmaceutically acceptable salt
thereof can be isolated using conventional methods.
Reaction Scheme VII
XUV
XLV
(3)
R 4 -Q
XLVI
In some embodiments, compounds of the invention can be prepared according to
Reaction Scheme VIII, wherein R, Ri, R2, and n are as described above.
In step (1) of Reaction Scheme VIII, the alkenylene bond in a l#-imidazo[4,5-
c]quinoline of Formula XLIV is reduced to provide a li/-imidazo[4,5-c]quinoline of
Formula XLVIL The reduction can be carried out as described in step (2) of Reaction
Scheme I.
In step (2) of Reaction Scheme VIII, the nitrile group in a l#-imidazo[4,5-
c]quinoline of Formula XL VII is hydrolyzed to provide a l#-imidazo[4,5-c]quinoline of
Formula XLVIII, which is a subgenus of Formulas I and II The reaction can be carried
out by treating a solution of a compound of Formula XL VII in a suitable solvent such as
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methanol with aqueous sodium hydroxide and aqueous hydrogen peroxide. The reaction
can be carried out at an elevated temperature, such as for example, 50 °C, and the product
or a pharmaceutical^ acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VIII
In some embodiments, compounds of the invention can be prepared according to
Reaction Scheme IX, wherein R, Ri, R 2 , R4, Rs, Z a , and n are as described above.
In step (1) of Reaction Scheme DC, the chloro group of a l/f-imidazo[4,5-
c]quinoline of Formula XXXIIa, which is a subgenus of Formula XXXII wherein LG is
chloro, is displaced with potassium thioacetate to provide a l#-imidazo[4,5-c]quinoline of
Formula XLIX. The reaction can be carried out at ambient temperature by adding
potassium thioacetate to a solution of a compound of Formula XXXIIa in a suitable
solvent such as DMF.
In step (2) of Reaction Scheme IX, the thioacetate group of a l//-imidazo[4,5-
c]quinoline of Formula XLIX is hydrolyzed under basic conditions to provide a thiol
substituted lif-imidazo[4,5-c]quinoline of Formula L. The reaction can be carried out by
adding a solution of sodium methoxide in methanol to a solution of a compound of
Formula XLIX in a suitable solvent such as methanol. The reaction can be carried out at
ambient temperature.
In step (3) of Reaction Scheme IX, the thiol group of a l#-imidazo[4,5-c]quinoline
of Formula L is oxidized to provide a sulfonyl chloride substituted l//-imidazo[4,5-
c]quinoline of Formula LI. The reaction can be carried out by adding a solution of sodium
chlorate in water to a solution of a compound of Formula L in hydrochloric acid. The
reaction can be carried out at a sub-ambient temperature, such as for example, 0 °C.
In step (4) of Reaction Scheme IX, a sulfonyl chloride substituted l//-imidazo[4,5-
c]quinoline of Formula LI is treated with an amine to provide a sulfonamide substituted
l/Wmidazo[4,5-c]quinoline of Formula LII, which is a subgenus of Formulas I and II.
The reaction can be carried out by adding an amine of Formula HN(R4)(Rs) to a
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compound of Formula LI in a suitable solvent such as dichloromethane or pyridine. The
reaction can be carried out at ambient temperature.
Reaction Scheme IX
In some embodiments, compounds of the invention can be prepared according to
Reaction Scheme X, wherein R, R u R 2 , R4, R$, Q, and n are as described above.
In step (1) of Reaction Scheme X, a vinyl substituted l/?-imidazo[4,5-c]quinoline
of Formula LIII undergoes ozonolysis to provide an aldehyde substituted l#-imidazo[4,5-
c]quinoline of Formula LIV. The reaction can be carried out by bubbling ozone through a
solution of a compound of Formula LIII in a suitable solvent such as dichloromethane and
then quenching with triphenylphosphine. The reaction can be carried out at a sub-ambient
temperature, such as 0 °C. Some vinyl substituted l#-imidazo[4,5-c]quinolines of
Formula LIII are known; others can be prepared using known synthetic methods. See for
example, U.S. Patent Application No. 2004/0147543 and the documents cited therein.
In step (2) of Reaction Scheme X, an aldehyde substituted li/-imidazo[4,5-
c]quinoline of Formula LIV is reduced to provide a hydroxy substituted l#-imidazo[4,5-
c]quinoline of Formula LV. The reaction can be carried out by treating a solution of a
compound of Formula LIV in a suitable solvent such as THF with sodium borohydride.
The reduction can be carried out at ambient temperature or at a sub-ambient temperature,
such as 0 °C.
In step (3) of Reaction Scheme X, a hydroxy substituted li/-imidazo[4,5-
c]quinoline of Formula LV is chlorinated using conventional methods to provide a chloro
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substituted l#-imidazo[4,5-c]quinoline of Formula LVL The reaction can be carried out
by treating a solution of a compound of Formula LV in a suitable solvent such as
dichloromethane with thionyl chloride.
In step (4) of Reaction Scheme X, the chloro group of a l#-imidazo[4,5-
cjquinoline of Formula LVI is displaced to provide an azido substituted l#-imidazo[4,5-
c]quinoline of Formula LVII. The reaction can be carried out by treating a solution of a
compound of Formula LVI in a suitable solvent such as DMF with sodium azide.
In step (5) of Reaction Scheme X, the azido group of a li/-imidazo[4,5-c]quinoline
of Formula LVII is reduced to provide an aminomethyl substituted l/f-imidazo^j.S-
c]quinoline of Formula LVIIL The reduction can be carried out using conventional
methods such as, for example, catalytic hydrogenation.
In step (6) of Reaction Scheme X, the amino group of a l//-imidazo[4,5-
c]quinoline of Formula LVIII is further elaborated using the methods described in step (6)
of Reaction Scheme IV to provide l£Mmidazo[4,5-c]quinoline of Formula LIX, which is a
subgenus of Formulas I and II. The product or a pharmaceutical^ acceptable salt thereof
can be isolated using conventional methods.
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Reaction Scheme X
R e LIX
For certain embodiments, compounds of the invention can be prepared according
to Reaction Scheme XI, wherein Ra, Rb, Ri, R2, and G are as defined above. Compounds
5 of Formula la can be prepared according to the methods described above. The amino
group of a compound of Formula la can be converted by conventional methods to a
functional group such as an amide, carbamate, urea, amidine, or another hydrolyzable
group. A compound of this type can be made by the replacement of a hydrogen atom in an
amino group with a group such as -C(0)-R n \ a-aminoacyl, a-aminoacyl-a-aminoacyl,
1 0 -C(0)-0-R ,n , -C(0)-N(R ,m )-R"\ -C(=NY , )-R ! ", -CH(OH)-C(0)-OY', -CH(OC M alkyl)Y 0 ,
-CH 2 Yi, or -CH(CH 3 )Yi; wherein R ,n and R' m are each independently C MO alkyl,
C3.7 cycloalkyl, phenyl, or benzyl, each of which may be unsubstituted or substituted by
one or more substituents independently selected from the group consisting of halogen,
hydroxy, nitro, cyano, carboxy, Cm alkyl, Cm alkoxy, aryl, heteroaryl, arylC M alkylenyl,
15 heteroarylC M alkylenyl, haloC M alkylenyl, haloC M alkoxy, -0-C(0)-CH 3 , -C(0)-0-CH 3 ,
-C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 ; with the proviso that R ,,M may
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also be hydrogen; each a-aminoacyl group is independently selected from racemic, D, or
L-amino acids; Y 1 is hydrogen, C|. 6 alkyl, or benzyl; Y 0 is Cu alkyl,
carboxyC^alkylenyl, aminoCj^alkylenyl, mono-N-Cu6alkylaminoC M alkylenyl, or di-
A^i^-Ci^alkylaminoCMalkylenyl; and Y| is mono-//-C 1-6 alky lamino,
5 di-A^A^Ci^alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidin-l-yl, or
4-Ci^alkylpiperazin-l-yl. Particularly useful compounds of Formula XVI are amides
derived from carboxylic acids containing one to ten carbon atoms, amides derived from
amino acids, and carbamates containing one to ten carbon atoms. The reaction can be
carried out, for example, by combining a compound of Formula la with a chloroformate or
10 acid chloride, such as ethyl chloroformate or acetyl chloride, in the presence of a base such
as triethylamine in a suitable solvent such as dichloromethane at room temperature.
Reaction Scheme XI
la VII
Compounds of the invention can also be prepared using variations of the synthetic
1 5 routes shown in Reaction Schemes I through X that would be apparent to one of skill in
the art. For example, the synthetic routes shown in Reaction Schemes II through V for the
preparation of imidazoquinolines can be used to prepare imidazo[l,5]naphthyridines by
using a compound of Formula XLIII or XLI in lieu of a compound of Formula XV or
XVI. Also, the reduction shown in step (2) of Reaction Scheme III or IV may be
20 eliminated to provide compounds of the invention, wherein Z contains a carbon-carbon
double bond. Compounds of the invention can also be prepared using the synthetic routes
described in the EXAMPLES below.
Pharmaceutical Compositions and Biological Activity
25 Pharmaceutical compositions of the invention contain a therapeutically effective
amount of a compound or salt described above in combination with a pharmaceutical^
acceptable carrier.
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The terms "a therapeutically effective amount 55 and "effective amount" mean an
amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect,
such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral
activity. The exact amount of compound or salt used in a pharmaceutical composition of
5 the invention will vary according to factors known to those of skill in the art, such as the
physical and chemical nature of the compound or salt, the nature of the carrier, and the
intended dosing regimen.
In some embodiments, the compositions of the invention will contain sufficient
active ingredient or prodrug to provide a dose of about 100 nanograms per kilogram
1 0 (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably about 1 0 micrograms per
kilogram (|ng/kg) to about 5 mg/kg, of the compound or salt to the subject.
In other embodiments, the compositions of the invention will contain sufficient
active ingredient or prodrug to provide a dose of, for example, from about 0.01 mg/m 2 to
about 5.0 mg/m 2 , computed according to the Dubois method, in which the body surface
1 5 area of a subject (m 2 ) is computed using the subject's body weight: m 2 = (wt kg 0 ' 425 x
height cm 0,725 ) x 0.007184, although in some embodiments the methods may be performed
by administering a compound or salt or composition in a dose outside this range. In some
of these embodiments, the method includes administering sufficient compound to provide
a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of
20 from about 0.4 mg/m 2 to about 1 .2 mg/m 2 .
A variety of dosage forms may be used, such as tablets, lozenges, capsules,
parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal
patches, transmucosal patches and the like. These dosage forms can be prepared with
conventional pharmaceutical^ acceptable carriers and additives using conventional
25 methods, which generally include the step of bringing the active ingredient into
association with the carrier.
The compounds or salts of the invention can be administered as the single
therapeutic agent in the treatment regimen, or the compounds or salts described herein
may be administered in combination with one another or with other active agents,
30 including additional immune response modifiers, antivirals, antibiotics, antibodies,
proteins, peptides, oligonucleotides, etc.
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Compounds or salts of the invention have been shown to induce the production of
certain cytokines in experiments performed according to the tests set forth below. These
results indicate that the compounds or salts are useful for modulating the immune response
in a number of different ways, rendering them useful in the treatment of a variety of
5 disorders.
Cytokines whose production may be induced by the administration of compounds
or salts of the invention generally include interferon-a (IFN-a) and tumor necrosis factor-a
(TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may be
induced by compounds or salts of the invention include IFN-a, TNF-a, IL-1, IL-6, IL-10
10 and IL-1 2, and a variety of other cytokines. Among other effects, these and other
cytokines can inhibit virus production and tumor cell growth, making the compounds or
salts useful in the treatment of viral diseases and neoplastic diseases. Accordingly, the
invention provides a method of inducing cytokine biosynthesis in an animal comprising
administering an effective amount of a compound or salt of the invention to the animal.
1 5 The animal to which the compound or salt is administered for induction of cytokine
biosynthesis may have a disease as described infra, for example a viral disease or a
neoplastic disease, and administration of the compound or salt may provide therapeutic
treatment. Alternatively, the compound or salt may be administered to the animal prior to
the animal acquiring the disease so that administration of the compound or salt may
20 provide a prophylactic treatment.
In addition to the ability to induce the production of cytokines, compounds or salts
described herein can affect other aspects of the innate immune response. For example,
natural killer cell activity may be stimulated, an effect that may be due to cytokine
induction. The compounds or salts may also activate macrophages, which in turn
25 stimulate secretion of nitric oxide and the production of additional cytokines. Further, the
compounds or salts may cause proliferation and differentiation of B-lymphocytes.
Compounds or salts described herein can also have an effect on the acquired
immune response. For example, the production of the T helper type 1 (ThI) cytokine IFN-
y may be induced indirectly and the production of the T helper type 2 (T H 2) cytokines IL-
30 4, IL-5 and IL-1 3 may be inhibited upon administration of the compounds or salts.
Whether for prophylaxis or therapeutic treatment of a disease, and whether for
effecting innate or acquired immunity, the compound or salt or composition may be
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administered alone or in combination with one or more active components as in, for
example, a vaccine adjuvant. When administered with other components, the compound
or salt or composition and other component or components may be administered
separately; together but independently such as in a solution; or together and associated
5 with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a
colloidal suspension.
Conditions for which compounds or salts or compositions identified herein may be
used as treatments include, but are not limited to:
(a) viral diseases such as, for example, diseases resulting from infection by an
10 adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an
orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
(e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus
(e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus
(RSV)), a coronavirus (e.g., SARS), apapovavirus (e.g., papillomaviruses, such as those
1 5 that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B
virus), a flavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a
lentivirus such as HIV);
(b) bacterial diseases such as, for example, diseases resulting from infection by
bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus,
20 Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,
Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus,
Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia,
Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
(c) other infectious diseases, such as chlamydia, fungal diseases including but not
25 limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic
diseases including but not limited to malaria, Pneumocystis carnii pneumonia,
leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection;
(d) neoplastic diseases, such as intraepithelial neoplasias, cervical dysplasia,
actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma,
30 Kaposi's sarcoma, melanoma, leukemias including but not limited to acute myeloid
leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic
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leukemia, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous
T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers;
(e) TH2-mediated, atopic diseases, such as atopic dermatitis or eczema,
eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
5 (f) certain autoimmune diseases such as systemic lupus erythematosus, essential
thrombocythaemia, multiple sclerosis, discoid lupus, alopecia areata; and
(g) diseases associated with wound repair such as, for example, inhibition of keloid
formation and other types of scarring (e.g., enhancing wound healing, including chronic
wounds).
10 Additionally, a compound or salt identified herein may be useful as a vaccine
adjuvant for use in conjunction with any material that raises either humoral and/or cell
mediated immune response, such as, for example, live viral, bacterial, or parasitic
immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or
bacterial immunogens; toxoids; toxins; self-antigens; polysaccharides; proteins;
1 5 glycoproteins; peptides; cellular vaccines; DNA vaccines; autologous vaccines;
recombinant proteins; and the like, for use in connection with, for example, BCG, cholera,
plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B,
parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria,
hemophilus influenza b, tuberculosis, meningococcal and pneumococcal vaccines,
20 adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague,
HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial virus,
rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.
Compounds or salts identified herein may be particularly helpful in individuals
having compromised immune function. For example, compounds or salts may be used for
25 treating the opportunistic infections and tumors that occur after suppression of cell
mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
Thus, one or more of the above diseases or types of diseases, for example, a viral
disease or a neoplastic disease may be treated in an animal in need thereof (having the
disease) by administering a therapeutically effective amount of a compound or salt of the
30 invention to the animal.
An animal may also be vaccinated by administering an effective amount of a
compound or salt described herein, as a vaccine adjuvant. In one embodiment, there is
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provided a method of vaccinating an animal comprising administering an effective amount
of a compound or salt described herein to the animal as a vaccine adjuvant.
An amount of a compound or salt effective to induce cytokine biosynthesis is an
amount sufficient to cause one or more cell types, such as monocytes, macrophages,
5 dendritic cells and B-cells to produce an amount of one or more cytokines such as, for
example, IFN-ot, TNF-ot, IL-1, IL-6, IL-10 and IL-12 that is increased (induced) over a
background level of such cytokines. The precise amount will vary according to factors
known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 ^ig/kg to about 5 mg/kg. In other embodiments, the amount is
1 0 expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 ,
(computed according to the Dubois method as described above) although in some
embodiments the induction or inhibition of cytokine biosynthesis may be performed by
administering a compound or salt in a dose outside this range. In some of these
embodiments, the method includes administering sufficient compound or salt or
1 5 composition to provide a dose of from about 0. 1 mg/m 2 to about 2.0 mg/ m 2 to the subject,
for example, a dose of from about 0.4 mg/m 2 to about 1 .2 mg/m 2 .
The invention also provides a method of treating a viral infection in an animal and
a method of treating a neoplastic disease in an animal comprising administering an
effective amount of a compound or salt of the invention to the animal. An amount
20 effective to treat or inhibit a viral infection is an amount that will cause a reduction in one
or more of the manifestations of viral infection, such as viral lesions, viral load, rate of
virus production, and mortality as compared to untreated control animals. The precise
amount that is effective for such treatment will vary according to factors known in the art
but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10
25 Hg/kg to about 5 mg/kg. An amount of a compound or salt effective to treat a neoplastic
condition is an amount that will cause a reduction in tumor size or in the number of tumor
foci. Again, the precise amount will vary according to factors known in the art but is
expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 p,g/kg to
about 5 mg/kg. In other embodiments, the amount is expected to be a dose of, for
30 example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois
method as described above) although in some embodiments either of these methods may
be performed by administering a compound or salt in a dose outside this range. In some of
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these embodiments, the method includes administering sufficient compound or salt to
provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a
dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
In addition to the formulations and uses described specifically herein, other
formulations, uses, and administration devices suitable for compounds of the present
invention are described in, for example, International Publication Nos. WO 03/077944 and
WO 02/036592, U.S. Patent No. 6,245,776, and U.S. Publication Nos. 2003/0139364,
2003/185835, 2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858.
Objects and advantages of this invention are further illustrated by the following
examples, but the particular materials and amounts thereof recited in these examples, as well
as other conditions and details, should not be construed to unduly limit this invention.
EXAMPLES
Example 1
2-Ethoxymethyl- 1 -(3-isopropoxypropyl)-7-[(£)-2-(phenylthio)ethenyl]- li/-imidazo[4,5-
c]quinolin-4-amine
Part A
7-Bromo-4-chloro-3-nitroquinoline (40 g) was dissolved in dichloromethane (1.4
L) and triethylamine (23.3 mL). 3-Isopropoxypropylamine (19.3 mL) was added
dropwise. After 48 hours, the reaction mixture was washed successively with water and
saturated aqueous sodium chloride. The organic fraction was dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure. (7-Bromo-3-
nitroquinoIin-4-yl)-(3-isopropoxypropyl)amine was isolated as a tan solid (51.2g).
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PartB
(7-Bromo-3-nitroquinolin^-yl)-(3-isopropoxypropyl)amine (51 g) was slurried in
acetonitrile (750 mL) and added to a Parr flask containing 5% platinum on carbon (5 g).
The flask was degassed three times, then charged with hydrogen (30 psi) and shaken for 4
hours with replenishment of the hydrogen as necessary. The platinum catalyst was
removed by filtration through a bed of CELITE filter agent. The filtrate was evaporated to
afford 7-bromo-N 4 -(3-isopropoxypropyl)quinoline-3 5 4-diamine as a yellow oil (45 g).
PartC
7-Bromo-N 4 -(3-isopropoxypropyl)quinoline-3 5 4-diamine (45 g) was dissolved in
acetonitrile (1.3 L) and triethylamine (19.4 mL). Ethoxyacetyl chloride (18.0 g) was
added dropwise to the solution and the reaction was stirred for 16 hours. The solvent was
removed under reduced pressure to afford a tan solid. The solid was added to a solution of
ethanol (1 L) and triethylamine (77.5 mL) and heated at reflux for 4 hours. The solvent
was removed under reduced pressure. Water was added to the solid residue and the crude
product was recovered by filtration. Recrystallization from acetonitrile yielded 36.25 g of
7-bromo-2-ethoxymethyl-l-(3-isopropoxypropyl)-l/f-imidazo[4,5-c]quinoline as a tan
crystalline solid.
PartD
7-Bromo-2-ethoxymethyl-l-(3-isopropoxypropyl)-l/i r -imidazo[4 5 5-c]quinoline (20
g) was dissolved in chloroform (400 mL). 3-Chloroperoxybenzoic acid (60 % pure, 17.1
g) was added in 2 g portions over a 5 minute period and the reaction was stirred for 1 hour.
Ammonium hydroxide (300 mL) was added and the mixture was cooled to 5 °C with an
ice/water bath. p-Toluenesulfonyl chloride (9.4 g) was added at the rate of 1 g/min to
minimize gas evolution. After stirring for 16 hours, the layers were separated and the
aqueous fraction was extracted with chloroform. The combined organic fractions were
sequentially washed with 5% aqueous sodium bicarbonate, water and brine; dried over
anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel. The polar component of the
eluent was chloroform:methanol:ammonium hydroxide 80:1 8:2 (CMA). The purification
was carried out eluting with chloroform: CMA in a gradient from 98:2 to 88:12. The
material recovered from the column was recrystallized from acetonitrile to yield 7.0 g of
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7-bromo-2-ethoxymeth^
tan granular powder.
PartE
7-Bromo-2-ethoxymethyl-l-(3-isopropoxypropyl)-l#^^
5 ylamine (1 .00 g, 2.46 mmol), tris(2-tolyl)phosphine (1 6 mg, 0.05mmol) and a stir bar were
added to a pressure vessel. Palladium(II) acetate (6 mg, 0.025mmol), phenyl vinyl sulfide
(0.330 mL, 2.53 mmol) and triethylamine (0.685 mL, 4.92 mmol) were subsequently
added, followed by toluene (5 mL). The vessel was sealed with a TEFLON cap and the
reaction was heated at 1 10 °C for 40 hours. The reaction mixture was cooled to ambient
10 temperature and concentrated under reduced pressure. The residue was purified by flash
column chromatography (silica gel, eluting with a linear gradient of 1-7% methanol in
dichloromethane), followed by recrystallization from acetonitrile to provide 0.35 g of 2-
ethoxymethyl- 1 -(3-isopropoxypropyl)-7-[(£)-2-(phenylthio)etheny 1]- 1 #-imidazo[4,5-
c]quinolin-4-amine hydrobromide as yellow-orange crystals, mp 220-221 °C.
15 *H NMR (300 MHz, DMSO-^) S 13.16 (s, 1H), 9.2-8.1 (br s, 2H), 8.29 (d, J= 9.1 Hz,
1H), 7.93-7.73 (m, 2H), 7.57-7.32 (m, 6H), 6.90 (d, J= 15.6 Hz, 1H), 4.83 (s, 2H), 4.72-
4.67 (m, 2H), 3.64-3.51 (m, 5H), 2.15-2.02 (m, 2H), 1.18 (t, J= 7.0 Hz, 3H), 1.14 (d, J=
6.1 Hz, 6H);
HRMS (ESI) in/z 477.2323 (477.2324 calcd. for C27H32N4O2S, M+H);
20 Anal. Calcd. for CiT^WaS-HBr: C, 58.16; H, 5.97; N, 10.05; Br, 14.33. Found: C,
58.42; H, 6.49; N, 10.06; Br, 14.28.
Example 2
2-Ethoxymethyl-l-(3-isopropoxypropyl)-7-[(£)-2-(phenylsulfonyl)ethenyl]-l//-
imidazo[4,5-c]quinolin-4-amine
Part A
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7-Bromo-2-ethoxyme%M-(3^
(1.00 g, 2.46 mmol), phenyl vinyl sulfone (0.852 g, 5.06 mmol), palladium(II) acetate (12
mg, 0.05 mmol), and tris(2-tolyl)phosphine (32 mg, 0.10 mmol) were added to a pressure
tube. Triethylamine (1 .37 mL, 9.84 mmol) and acetonitrile (5 mL) were added. The tube
5 was flushed with nitrogen, sealed with a TEFLON plug and heated at 100 °C for 96 hours.
The reaction mixture was cooled to ambient temperature and concentrated under reduced
pressure. The residue was initially purified by flash column chromatography (silica gel,
eluting with a gradient of 50%-100% ethyl acetate in hexanes, followed by a gradient of
2%-6% methanol in ethyl acetate). Recrystallization of the resulting solid from acetonitrile
1 0 provided 0.600 g 7-(2-benzenesulfonylvinyl)-2-ethoxymethyl-l -(3-isopropoxypropyl)-l//-
imidazo[4,5-c]quinoline as a yellow crystalline solid.
PartB
7-(2-Benzenesulfonyl vinyl)-2-ethoxymethyl- 1 -(3 -i sopropoxy propyl)- 1 H-
imidazo[4,5-c]quinoline (0.600 g, 1.22 mmol) was dissolved in chloroform (12 mL). 3-
15 Chloroperoxybenzoic acid (60% purity, 0.351 g, 1.22 mmol) was added. The reaction was
stirred for 30 minutes. Ammonium hydroxide (8 mL) was added and the mixture was
stirred for 10 minutes. /?-Toluenesulfonyl chloride (0.232 g, 1.22 mmol) was added in one
portion and the reaction was stirred for an additional 16 hours. The layers were separated
and the aqueous fraction was extracted with chloroform. The combined organic fractions
20 were sequentially washed with water and saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography using a Horizon HPFC system (an automated,
modular high-performance flash purification product available from Biotage, Inc.;
Charlottesville, Virginia, USA). The polar component of the eluent was
25 chloroform:methanol:ammonium hydroxide 80: 1 8:2 (CM A). The purification was carried
out with a silica cartridge eluting with a linear gradient of 1-22% CMA in chloroform.
The resulting material was subsequently recrystallized from acetonitrile to yield 0.320 g 2-
ethoxymethyl- 1 -(34sopropoxypropyl)-7-[(^^
c]quinolin-4-amine as green needles, mp 188.5-190.0 °C.
30 ! H NMR (300 MHz, DMSO-afe) 6 8.20 (d, J = 8.6 Hz, 1H), 7.98-7.92 (m, 3H), 7.81-7.60
(m, 6H), 6.76 (s, 2H), 4.78 (s, 2H), 4.67-4.62 (m, 2H), 3.63-3.44 (m, 5H), 2.13-1.98 (m,
2H), 1.16 (t, J= 7.0 Hz, 3H), 1.15 (d, J= 6.1 Hz, 6H);
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HRMS (ESI) m/z 509.2218 (509.2223 calcd. for C27H32N4O4S, M+H);
Anal Calcd. for C27H 3 2N 4 O 4 S-0.8H2O: C, 62.02; H, 6.47; N, 10.72; S, 6.13. Found: C,
62.03; H, 6.52; N, 10.73; S, 6.12.
Example 3
N- [4-Amino-2-ethoxy methyl- 1 -(3 -isopropoxypropy 1)- 1 fl-imidazo [4,5-c]quinolin-7-yl]-2-
methylpropanamide
7-Bromo-2-ethoxymethyl-l-(3-isopropoxyprop
(0.5 g, 1.23 mmol), potassium phosphate (0.548 g, 2.58 mmol), isobutyramide (0.128 g,
1.48 mmol), copper(I) iodide (46 mg, 0.246 mmol), and trans-(±)-l,2-diaminocyclohexane
were added to a 2 dram vial. Dioxane (1.2 mL) and a stir bar were added and the vial was
sealed with a TEFLON lined cap. The vial was heated at 1 10 °C for 16 hours. The
reaction was cooled to ambient temperature and then diluted with water and chloroform.
The layers were separated and the organic fraction was washed with water and saturated
aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. Purification using a HORIZON HPFC
system (silica cartridge, eluting with a linear gradient of 2-23% CMA in chloroform)
provided 0.402 g of A/-[2-ethoxymethyl-l-(3-isopropxypropyl)-l//-imidazo[4,5-
c]quino!in-7-yl]-2-methylpropanamide as a yellowish waxy solid.
PartB
7/-[2-ethoxymethyl-l-(3-isopropxypropyl)-l//-imidazo[4,5-c]quinolin-7-yl]-2-
methylpropanamide (0.400 g, 0.98 mmol) was dissolved in chloroform (10 mL). 3-
Chloroperoxybenzoic acid (60% purity, 0.532 g, 1.85 mmol) was added in two portions 30
minutes apart. The reaction was stirred for an additional 30 minutes. Ammonium
hydroxide (10 mL) was added and the reaction was stirred for 10 minutes.
Benzenesulfonyl chloride (0.236 mL, 1.8 mmol) was added in one portion and the reaction
Part A
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was stirred for 72 hours. The layers were separated and the aqueous fraction was
extracted with chloroform. The combined organic fractions were sequentially washed
with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. Purification using a HORIZON HPFC
system (silica cartridge, eluting with a linear gradient of 2-25% CMA in chloroform),
followed by recrystallization from acetonitrile provided 0.130 g of N-[4-amino-2-
ethoxymethyl- 1 -(3-isopropxypropyl)-l //-imidazo[4,5-c]quinolin-7-yl]-2-
methylpropanamide as a beige solid, mp 214-215 °C.
! H NMR (300 MHz, DMSO-^) 5 9.88 (s, 1H), 8.1 1 (d, 7= 8.9 Hz, 1H), 7.96 (d, J= 2.1
Hz, 1H), 7.51 (dd, 7= 8.9, 2.1 Hz, 1H), 6.52 (s, 2H), 4.75 (s, 2H), 4.62-4.57 (m, 2H), 3.65-
3.48 (m, 5H), 2.73-2.58 (m, 1H), 2.15-2.00 (m, 2H), 1.18-1.12 (m, 15H);
13 CNMR(75 MHz, DMSO-^) 5 175.2, 152.2, 148.3, 145.9, 138.3, 133.1, 120.7, 115.0,
114.0, 110.4, 70.7, 65.3, 64.0, 63.9, 42.8, 35.0, 30.3, 22.0, 19.5, 14.9;
MS (ESI) m/z 428.2657 (428.2662 calcd. for C23H33N5O3, M+H);
Anal. Calcd. for 023^3^03*0.25^0: C, 63.94; H, 7.82; N, 16.21. Found: C, 64.02; H,
8.10; N, 16.25.
Example 4
JV-[4-Amino-2-ethoxymethyl- 1 -(2-ty
7-yl]ethanesulfonamide
The general method described in Part A of Example 3 was followed using 7-
bromo-2-ethoxymethyl-l-(2-hydroxy-2-methylpropyl)-l/f-imidazo[4,5-c]quinolin-4-
amine (U.S. Patent Application Publication No. US 2004/0147543 , Examples 125-135) in
lieu of 7-bromo-2-ethoxymethyl-l-(3-isopropoxypropyl)-l//-imidazo[4,5-c]quinoline and
ethanesulfonamide in lieu of isobutyramide. Purification using a HORIZON HPFC
system (silica cartridge, eluting with a linear gradient of 2-25% CMA in chloroform),
followed by recrystallization from acetonitrile afforded 0.108 g of A^-[4-amino-2-
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ethoxymethyl-l<2-hydroxy-2-methylpropyl)-li/-imidazo[4,5-c]quinolin-7-
yl]ethanesulfonamide as white crystals, mp 124.0-127.0 °C.
'H NMR (300 MHz, DMSO-cfc) 5 9.85 (s, 1H), 8.21 (d, J= 9.0 Hz, 1H), 7.44 (d, J= 2.4
Hz, 1H), 7.1 1 (dd, J= 8.9, 2.3 Hz, 1H), 6.56 (s, 2H), 5.05-4.73 (br s, 1H), 4.86 (s, 2H),
5 4.62 (s, 2H), 3.50 (q, J= 7.0 Hz, 2H), 3.11 (q, J= 7.3 Hz, 2H), 1.21 (t, J= 7.3 Hz, 3H),
1.17 (br s, 6H), 1.13 (t, J= 7.0 Hz, 3H);
13 CNMR (125 MHz, DMSO-tf tf ) 6 152.4, 150.4, 146.2, 136.9, 134.2, 125.4, 122.5, 114.7,
1 13.1, 1 1 1.6, 70.6, 65.2, 64.8, 54.7, 44.9, 27.5, 15.0, 8.0;
MS (APCI) m/z 422 (M+H) + ;
10 Anal. Calcd. for Cis^NsC^S'O^SHiO: C, 53.57; H, 6.51; N, 16.44; S, 7.53. Found: C,
53.28; H, 6.72; N, 16.58; S, 7.42.
Example 5
AT-{4-[4-Amino-2-ethoxymethyl-l-(3-isopropxypropyl)-l^-imidazo[4,5-c]quinolin-7-
yl]butyl}acetamide
Part A
7-Bromo-2-emoxymethyl-l-(3-isopropoxypropyl)-l/T-irnidazo[4,5-c]quinoline
(1.9 g, 4.68 mmol), 2-but-3-enyl-l#-isoindole-l,3(2//)-dione (1.04 g, 5.15 mmol), cesium
carbonate (3.05 g, 9.36 mmol), triphenylphosphine (0.246 g, 0.94 mmol), palladium(II)
20 acetate (0. 1 05 g, 0.47 mmol),and JV^-dimethylformamide (DMF) (28 mL) were added to
a pressure tube. The vessel was sealed with a TEFLON cap and heated at 140 °C for 2.5
hours. The reaction was cooled to ambient temperature. The reaction was diluted with
ethyl acetate and washed multiple times with water. The initial water wash was extracted
with ethyl acetate. The organic fractions were combined and washed with water once
25 again. The organic fractions were concentrated under reduced pressure and the residue
was purified using a HORIZON HPFC system (silica cartridge, eluting with a linear
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gradient of 2-20% CMA in chloroform) to yield 1.9 g of 2-{(3^-4-[2-ethoxymethyl-l-(3-
isopropoxypropyl)-l#-imidazo[4,5-c]quinolin^^
dione as a pale yellow oil.
PartB
5 2- {(3£)-4-[2-ethoxymethyl- 1 -(3 -isopropoxypropyl)- 1 i/-imidazo[4,5 -c]quinolin-7-
yl]but-3-enyl}-l^isoindole-l,3(2//)-dione (1.9 g, 3.6 mmol) was dissolved in ethanol (50
mL) and added to a Parr flask containing 10% palladium on carbon (0.3 g) wetted with
ethanol. The flask was degassed three times, charged with hydrogen (50 psi) and shaken
for 16 hours. The catalyst was removed by filtration through CELITE filter agent.
1 0 Concentration of the filtrate under reduced pressure provided 1 .9 g of 2-{4-[2-
ethoxymethyl-1 -(3-isopropoxypropyl)- 1^
isoindole-l,3(2#)-dione as a pale yellow oil.
PartC
2-{4-[2-(ethoxymethyl)-l-(3-isopropoxypropyl)-liy-imidazo[4,5-c]quinolin-7-
1 5 yl]butyl}-l/Wsoindole- 1 ,3(2#)-dione (1 .5 g, 2.84 mmol) was dissolved in ethyl acetate
(15 mL) and heated to 50 °C. 33% Peracetic acid in acetic acid (0.60 mL, 2.84 mmol) was
added and the solution was stirred for 3 hours. Another 0.2 mL peracetic acid was added
and the reaction was stirred for 1 hour. The mixture was cooled to ambient temperature
and quenched with aqueous sodium metabisulfite (0.593 g in 1.2 mL water). The solution
20 was made basic with saturated aqueous sodium carbonate. The mixture was diluted with
water and the layers were separated. The aqueous fraction was extracted with ethyl
acetate. The organic fractions were combined and concentrated under reduced pressure.
The resulting yellow foam was dissolved in dichloromethane (15 mL) and ammonium
hydroxide (10 mL). /?-Toluenesulfonyl chloride (0.541 g, 2.84 mmol) was added in one
25 portion. The mixture was stirred for 70 hours. The layers were separated and the aqueous
fraction was extracted with dichloromethane. The organic fractions were combined and
concentrated under reduced pressure to yield 0.525 g of 2-{4-[4-amino-2-ethoxymethyl-l-
(3 -isopropoxypropyl)- 1 //-imidazo[4,5 -c]quinolin-7-yl]butyl } - 1 tf-isoindole- 1 ,3 (2//)-dione
as a yellow oil.
30 PartD
2-{4-[4-amino-2-ethoxymethyl-l-(3-isopropoxypropyl)-l^-imidazo[4,5-
c]quinolin-7-yl]butyl}-l//-isoindole-l,3(27i0-dione (1.15 g, 2.1 mmol) was dissolved in
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ethanol (36 mL. Hydrazine (0372 mL, 1 1.4 mmol) was added and the solution was
heated at reflux temperature for 1 hour. The resulting white slurry was cooled to ambient
temperature and filtered. The solid showed 40% product by NMR. The solid was saved
and used in Part E. The filtrate was concentrated under reduced pressure and purified
5 using a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-20%
CMA in chloroform) to provide 0.21 1 g of 7-(4-aminobutyl)-2-ethoxymethyl-l-(3-
isopropoxypropyl)-lii/-imidazo[4 > 5-c]quinolin-4-amine as a white solid.
PartE
The crude mixture of 7-(4-aminobutyl)-2-ethoxymethyl-l-(3-isopropoxypropyl)-
10 l//-imidazo[4,5-c]quinolin-4-amine from Part D was slurried in chloroform (7 mL) and
triethylamine (0.185 mL, 1.32 mmol). Acetic anhydride (0.061 mL, 1.32 mmol) was
added and the mixture was stirred for 16 hours. The resulting solution was concentrated
under reduced pressure and the residue was purified using a HORIZON HPFC system
(silica cartridge, eluting with a linear gradient of 1-20% CMA in chloroform). The
15 diacylated product was dissolved in methanol (10 mL) and concentrated hydrochloric acid
(2 mL). The mixture was heated to reflux for 2 hours and then cooled to ambient
temperature. Saturated aqueous sodium carbonate was added to make the reaction basic.
The methanol was evaporated under reduced pressure and the residue was extracted with
. dichloromethane (2x100 mL). The combined organic fractions were dried over sodium
20 sulfate, filtered, and concentrated under reduced pressure. The residue was purified using
a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-15% CMA
in chloroform). Subsequent crystallization from ethyl acetate and hexanes provided 0.192
g of A^4-[4-amino~2-ethoxyme%l-H3^
yl]butyl}acetamide as flocculent white crystals, mp 122-124 °C.
25 'HNMR (300 MHz, DMSO-^) 5 8.10 (d, J= 8.4 Hz, 1H), 7.79 (t, J= 4.8 Hz, 1H), 7.42
(d,7= 1.1Hz, 1H), 7.09 (dd, J= 8.3, 1.3 Hz, 1H), 6.51 (s, 2H), 4.76 (s, 2H), 4.64-4.59 (m,
2H), 3.64-3.47 (m 5 5H), 3.09-3.03 (m, 2H), 2.69 (t, J= 7.4 Hz, 2H), 2.15-2.01 (m, 2H),
1.78 (s, 3H), 1.68-1.59 (m, 2H), 1.48-1.36 (m, 2H) 9 1.16 (t,J= 7.0 Hz, 3H), 1.15 (d,J =
6.2 Hz, 6H);
30 13 CNMR(125MHz,DMSO-4j)5 168.8, 152.0, 148.5, 145.3, 140.7, 133.1, 125.8, 125.3,
122.0, 120.4, 1 12.6, 70.8, 65.4, 64.1, 63.9, 42.8, 38.3, 34.8, 30.3, 28.8, 28.3, 22.6, 22.0,
14.9;
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MS (ESI) m/z 456 (M+H) + ;
Anal. Calcd. for C2SH37N5O3: C, 65.91; H, 8.19; N, 15.37. Found: C, 65.62; H, 7.94; N,
15.42.
Example 6
M-{4-[4-Ammo-2-emoxymethyl-l-(3-isopropxypropyl)-l^
yl]butyl } -N '-propy lurea
7-(4-Aminobutyl)-2-ethoxymethyl-l-(3-isopropoxypropyl)-li/-imidazo[4,5-
c]quinolin-4-amine (0.250 g, 0.604 mmol) was dissolved in dichloromethane. Propyl
isocyanate (0.060 mL, 0.604 mmol) was added and the reaction was stirred for 16 hours.
A feathery solid was produced. The dichloromethane was removed under reduced
pressure. The residue was diluted (not dissolved) in acetonitrile. This altered the solid to
a more granular form. The solid was filtered, washed with acetonitrile, and dried to yield
0.090 g of N- {4-[4-Amino-2-ethoxymethyl- 1 -(3-isopropxypropyl)- 1 #-imidazo[4,5-
c]quinolin-7-yl]butyl}-N'-propylurea as an off-white solid, mp 134.5-135.5 °C.
'H NMR (300 MHz, DMSO-rf*) 5 8.10 (d, J= 8.4 Hz, 1H), 7.42 (s, 1H), 7.09 (dd, J= 8.3,
1.2 Hz, 1H), 6.50 (s, 2H), 5.75 (t, J= 5.4 Hz, 1H), 5.71 (t, J= 5.7 Hz, 1H), 4.76 (s, 2H),
4.63-4.60 (m, 2H), 3.62-3.54 (m, 3H), 3.49 (t, J= 5.5 Hz, 2H), 3.03-2.99 (m, 2H), 2.92 (q,
/= 6.5 Hz, 2H), 2.68 (t, J= 7.5 Hz, 2H), 2.1 1-2.04 (m, 2H), 1.65-1.59 (m, 2H), 1.44-1.31
(m, 4H), 1.77-1.15 (m, 9H), 0.81 (t, J= 7.4 Hz, 3H);
13 CNMR(125 MHz, DMSO-rf tf ) 6 158.0, 151.9, 148.5, 145.4, 140.8, 133.1, 125.8, 125.3,
122.1, 120.4, 112.5, 70.8, 65.3, 64.1, 63.9, 42.8, 41.0, 34.9, 30.3, 29.7, 28.3, 23.2, 22.0,
14.9,11.3;
MS (APCI) m/z 499 (M+H) + ;
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Anal. Calcd. for C27H42N6O3; C, 65.03; H, 8.49; N, 16.85. Found: C, 64.90; H, 8.38; N,
16.84.
Example 7
2-Ethoxymethyl-l -(3-methoxyp^
7-Bromo-2-ethoxymethyl-H3-methoxypropyl)-^ (U.S.
Patent Application Publication No. US 2004/0147543 Examples 163-175, 1.0 g, 2.64
mmol) and sodium thiomethoxide (0.185 g, 2.64 mmol) were dissolved in NJsf-
dimethylformamide (25 mL). The reaction mixture was stirred at ambient temperature for
20 minutes and then heated at 55 °C for 16 hours. The reaction was cooled to ambient
temperature and the solvent was removed under reduced pressure. The residue was
dissolved in dichloromethane and sequentially washed with water and saturated aqueous
sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. 2-Ethoxymethyl-l -(3-methoxypropyl)-7-methylthio-li/-imidazo[4,5-
c]quinoline was isolated as 1.1 g of a pale yellow oil.
PartB
The crude oil from Part A was dissolved in chloroform (20 mL). 3-
Chloroperoxybenzoic acid (60% pure, 1.96 g, 6.84 mmol) was added in one portion. After
30 minutes, an additional 0.5 g of 3-chloroperoxybenzoic acid and 5 mL of chloroform
was added. After 20 minutes, the reaction mixture was poured into a separately funnel
and washed with saturated aqueous sodium carbonate. The aqueous fraction was extracted
sequentially with dichloromethane, chloroform, and 9:1 chloroform/methanol. The
combined organic fractions were sequentially washed with water and saturated aqueous
sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified using a HORIZON HPFC system (silica cartridge,
amine
Part A
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eluting with a linear gradient of 2-30% CMA in chloroform). Fractions containing
oxidized product were combined and concentrated. The residue was dissolved
dichloromethane (15 mL) and diluted with ammonium hydroxide (10 mL). p~
Toluenesulfonyl chloride was added to the mixture and the reaction was stirred for 120
hours. The layers were separated and the aqueous fraction was extracted with
dichloromethane. The combined organic fractions were sequentially washed with water
and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. Purification using a HORIZON HPFC system
(silica cartridge, eluting with a linear gradient of 1-20 % CMA in chloroform), followed
by recrystallization from acetonitrile yielded 0.357 g of 2-ethoxymethyl-l-(3-
methoxypropyl)-7-methylsulfonyl-l//-imidazo[4,5-c]quinolin-4-amine as white needles,
mp 166.5-167.5 °C.
*H NMR (300 MHz, DMSO-^) 8 8.34 (d, J= 8.7 Hz, 1H), 8.07 (d, J= 2.0 Hz, 1H), 7.70
(dd, J= 8.6, 1.9 Hz, 1H), 7.03 (s, 2H), 4.80 (s, 2H), 4.71-4.66 (m, 2H), 3.57 (q, 7.0 Hz,
2H), 3.47 (t, J= 5.6 Hz, 2H), 3.31 (s, 3H), 3.28 (s, 3H), 2.15-2.07 (m, 2H), 1.17 (t, 7= 7.0
,3 CNMR (75 MHz,DMSO-^)5 153.3, 150.3, 144.6, 138.5, 132.3, 127.8, 124.9, 121.8,
1 17.8, 1 17.7, 68.6, 65.5, 64.0, 58.1, 43.7, 43.0, 29.7, 14.9;
MS (ESI) m/z 393.1602 (393.1597 calcd. for C18H24N4O4S, M+H);
Anal. Calcd. for C 18 H 2 4N 4 04S: C, 55.09; H, 6.16; N, 14.28; S, 8.17. Found: C, 55.12; H,
6.02; N, 14.32; S, 8.26.
Example 8
Methyl (2^0-[4-amino-2-butyl-l-(2-methylpropyl)-liy-imidazo[4,5-c]quinolin-7-
yl]prop-2-enoate
A thick walled glass tube, equipped with stir bar, was charged with palladium (II)
acetate (18 mg, 0.08 mmol), acetonitrile (2 mL), methyl acrylate (69 mg, 0.8 mmol),
triethylamine (240 mg, 2.4 mmol), tri-o-tolylphosphine (49 mg, 0.16 mmol) and 7-bromo-
Hz, 3H);
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2-butyl-l-(2-methylpropyl)-l//-imid^ (U.S. Patent Application
Publication No. US 2004/0147543 Example 1, 300 mg, 0.8 mmol). The reaction mixture
was purged with nitrogen and the tube was sealed and heated to 100 °C in an oil bath. The
mixture became an amber homogeneous solution after approximately 5 minutes. The
5 reaction was maintained at 100 °C for 32 hours and then concentrated to dryness. The
reaction mixture was taken up in water and dichloromethane. Saturated aqueous
potassium carbonate solution was added, adjusting to pH 1 1 . The organic layer was
separated and concentrated to a golden syrup. The crude product was purified by flash
chromatography on silica gel (eluting with 5% methanol/dichloromethane). The resulting
1 0 tan solid (230 mg) was recrystallized from acetonitrile to give 220 mg of methyl (2E)^
[4-amino-2-butyl-l-(2-methylpropyl>^ as a
pale gold solid, mp 193-194 °C.
MS (APCI) m/z 381.5 (M + H) + .
1 5 Methyl (2£)-3-[4-amino- 1 -[4-(l , 1 -dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)- 1 H-
A 50-mL thick walled glass vessel was charged with palladium (II) acetate (67 mg,
0.3 mmol), acetonitrile (2 mL), methyl acrylate (0.26 g, 3.0 mmol), triethylamine (0.9 g,
20 9.0 mmol), tri-o-tolylphosphine (0.18 g, 0.6 mmol) and 7-bromo-l-[4-(l,l-
dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxym
(U.S. Patent Application Publication No. US 2004/0147543 Example 152-156, 1.5 g, 3.0
mmol). An additional 13 mL of acetonitrile was added. The reaction mixture was purged
with nitrogen then heated to 90 °C. The turbid orange mixture was maintained at 90 °C
25 overnight. Anhydrous DMF (30 mL) was added to dissolve the 7-bromoquinoline starting
material. The reaction was then heated at 120 °C overnight. The reaction mixture was
filtered to remove the catalyst then concentrated to dryness. The desired product was
Example 9
imidazo[4,5-c]quinolin-7-yl]prop-2-enoate
NH 2 .
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isolated by column chromatography on silica gel (eluting with a gradient of 2%-8%
methanol in dichloromethane). The resulting peach solid was taken up in saturated
potassium carbonate solution and dichloromethane and stirred overnight at ambient
temperature. The organic layer was separated and concentrated to dryness. The residue
was recrystallized from acetonitrile to yield 0.65 g of methyl (2£)-3-[4-amino-l-[4-(l 5 l-
dioxidoisotWazolidin-2-yl)butyl]-2-(ethoxy
2-enoate as a pale yellow solid, mp 162-163 °C.
MS (ACPI) m/z 502.2 (M+H) + .
Anal. Calcd. for C24H31N5O5S: C, 57.47; H, 6.23; N, 13.96. Found: C, 57.21; H, 6.38; N,
14.14.
Example 10
1 - {3-[4-Amino4 -(2-methylpm
one
A thick walled glass tube, equipped with stir bar, was charged with palladium (II)
acetate (67 mg, 0.3 mmol), acetonitrile (15 mL), N-allyl-2-pyrrolidone (650 mg, 5.17
mmol), triethylamine (2.1 ml, 15.65 mmol), tri-o-tolylphosphine (275 mg, 0.9 mmol) and
8-bromo4-(2-methylpropyl)-l//-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application
Publication No. US 2004/0147543 Example 11, 1.5 g, 4.7 mmol). The reaction mixture
was purged with nitrogen, sealed and heated at 120 °C for 24 hours. The reaction mixture
was concentrated to dryness. The reaction mixture was slurried in a mixture of 1%
aqueous sodium carbonate (75 mL) and chloroform (100 mL). The layers were separated.
The aqueous layer was extracted with chloroform (2 x 25 mL). The combined organic
fractions were concentrated to dryness and purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane) to provide
Part A
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1 - {(2^-3 -[4-amino4 <2-me%^
enyl}pyrrolidin-2-one.
PartB
A glass Parr vessel was charged with 10% palladium on carbon catalyst (0.1 g),
methanol (50 mL), ethanol (50 mL) and l-{(2£0-3-[4-amino-l-(2-methylpropyl)-l//-
imidazo[4 > 5-c]quinolin~8-yl]prop-2-enyl}pyrrolidin-2-one. The vessel was evacuated and
charged with hydrogen gas (51 psi, 3.4 x 10 5 Pa). The reaction was shaken at ambient
temperature overnight (approximately 18 hours). The reaction mixture was filtered to
remove the catalyst and concentrated to dryness. The crude product was purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8%
methanol in dichloromethane) followed by recrystallization from acetonitrile to yield 300
mg of l-{3-[4-amino-l-(2-methylpropyl)-l//-imidazo[4 > 5-c]quinolin-8-
yl]propyl}pyrrolidin-2-one as a white solid, mp 174-175 °C.
MS (APCI) m/z=366 (M+H) + ;
Anal. Calcd. for C21H27N5O: C, 69.01; H, 7.45; N, 19.16. Found: C, 68.83; H, 7.71; N,
19.42.
Example 1 1
Methyl (2£)-3-[4-amino-2-(ethoxymethyl)- 1 -(2-hydroxy-2-methylpropyl)-l#-
imidazo[4,5-c]quinolin-7-yl]prop-2-enoate
A thick walled glass reaction vessel was charged with anhydrous DMF (2 mL),
palladium (II) Acetate (0.01 equivalents (eq)), tri-o-tolylphosphine (0.02 eq) and
triethylamine (3 eq). To this orange solution was added a solution of l-[4-amino-7-
bromo-2-(ethoxymethyl)-l//-imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol in 50 mL
anhydrous DMF followed by the addition of methyl acrylate (1.0 eq). The reaction
mixture was purged with nitrogen, sealed and heated at 120 °C overnight, and slowly
cooled to room temperature. The reaction mixture was concentrated to dryness and then
slurried in water (50 mL). Saturated potassium carbonate solution (25 mL) was added.
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The mixture was extracted with dichloromethane (4 x 50 mL). The combined extracts
were concentrated under reduced pressure and purified by chromatography using a
HORIZON HPFC system (silica cartridge, eluting with 0-25% CMA in chloroform) to
provide methyl (2£)-3-[4-ammo-2-(ethoxyme%^
imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a white solid.
Example 12
Methyl 3-[4-amino-2-(ethoxymethyl)4-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5-
c]quinolin-7-yl]propanoate
A glass Parr vessel was charged with 10% palladium on carbon catalyst (0.35 g,
0.1 eq. weight/weight (w/w)), methanol (50 mL) ethanol (50 ml) and methyl (2E)-3-[4-
amino-2-(ethoxymethy 1)- 1 -(2-hydroxy-2-methy lpropyl)- 1 tf-imidazo [4,5 -c]quinolin-7-
yl]prop-2-enoate (3.5 g, 8.8 mmol). The vessel was evacuated and charged with hydrogen
gas (45 psi, 3.1 x 10 5 Pa). The reaction was shaken at ambient temperature overnight
(approximately 1 8 hours). The reaction mixture was filtered to remove the catalyst and
concentrated to dryness. The crude product was purified by chromatography using a
HORIZON HPFC system (silica cartridge, eluting with 0-30% CMA in chloroform)
followed by recrystallization from acetonitrile to provide methyl 3-[4-amino-2-
(ethoxymethyl)- 1 -(2-hydroxy-2-methylpropyl)- 1 H-imidazo[4,5 -c]quinolin-7-
yl]propanoate as a white solid.
3-[4-Amino-2-(ethoxymethyl)-l-(2-hydro^
NH 2
J
Example 13
7-yl]propanoic acid
NH 2
OH
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A 100-mL round bottom flask was charged with methyl 3-[4-amino-2-
(ethoxymethyl)- 1 -(2-hydroxy-2-methylpropy 1)- 1 //-imidazo [4,5-c]quinolin-7-
yljpropanoate (0.28 g, 0.7 mmol) and Claisen's alkali (4.0 mL), and the reaction was
stirred at ambient temperature for one hour and then concentrated to a colorless syrup.
5 Citric acid solution (25 mL of 1 0% aqueous) was added. A white precipitate formed. The
mixture was stirred for 15 minutes, and then the solid was collected by vacuum filtration
to yield 0.25 g of 3-[4-amino-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-lH-
imidazo[4,5-c]quinolin-7-yl]propanoic acid.
10 H4-Amino-2-(ethoxymethyl)-7^ [4 3 5-c]
quinolin- 1 -yl]-2-methy lpropan-2-ol
A 20-ml glass vial was charged with anhydrous DMF (1 mL), 3-[4-amino-2-
(ethoxy methyl)- 1 -(2-hydroxy-2-methylpropyl)- 1 77-imidazo [4,5-c] quinolin-7-yl]propanoic
15 acid (165 mg, 0.43 mmol), N-(3 -dimethyl aminopropyl)-N"-ethylcarbodiimide
hydrochloride (100 mg, 0.52 mmol, 1.3 eq), 1-hydroxybenzotriazole (70.3 mg, 0.52 mmol,
1 .3 eq), and morpholine (1 10 mg, 1 .29 mmol, 3.0 eq). The reaction was maintained at
ambient temperature overnight. The reaction mixture was poured into water (10 mL), and
the resulting mixture was extracted with dichloromethane (3x10 mL). The chloroform
20 fractions were combined and concentrated, and the residue was purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30%
CMA in chloroform) followed by recrystallization from acetonitrile to provide l-[4-
amino-2-(ethoxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-lH-imidazo [4,5-c] quinolin-
l-ylJ-2-methylpropan-2-ol as awhite solid, mp 118-119 °C.
25 MS (APCI) rn/z 456 (M+H) + .
Example 14
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Example 15
Methyl (2^-3-[4-amino-H2-hydroxy-2-me%^
yl]prop-2-enoate
To a suspension of 7-bromo-4-cMoro-3-nitroquinoline (U.S. Patent Application
Publication No. US 2004/0147543 Example 1, 54.2 g, 0.19 mol) in dichloromethane (1 L)
was added triethylamine (100 mL, 0.72 mol., 3.8 eq) in one portion. To the resulting
solution was slowly added hydroxyisobutylamine (18.44 g, 0.21 mol 5 1.1 eq). The
reaction was complete within two hours. The reaction mixture was concentrated to
dryness, and the residue was slurried in a solution of 1% aqueous sodium carbonate (600
mL) for two hours. The resulting bright yellow solid was collected by vacuum filtration
and dried on the filter funnel overnight to provide 57 g of l-(7-bromo-3-nitroquinolin-4-
ylamino)-2-methylpropan-2-ol.
PartB
A glass Parr vessel was charged with 5% platinum on carbon catalyst (5 g), l-(7-
bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol (57 g, 0.17 mol), and a 1:1
solution of acetonitrile/toluene (1800 mL). The vessel was evacuated, charged with
hydrogen gas (50 psi, 3.4 x 10 5 Pa), and shaken for 5 hours. The reaction mixture was
then filtered through a 0.2 micron polytetrafluoroethylene (PTFE) membrane filter. The
filtrate was concentrated to provide 49 g of l-[(3-amino-7-bromoquinolin-4-yl)amino]-2-
methylpropan-2-ol as a bright yellow-orange solid.
A 2-L round bottom flask was charged with l-[(3-amino-7-bromoquinolin-4-
yl)amino]-2-methylpropan-2-ol (25.5 g, 82.2 mmol), toluene (1 L), pyridine-HCl (0.1 g,
0.82 mmol, 0.01 eq) and triethylorthoformate (13.4 g, 90.4 mmol, LI eq), and the reaction
was heated at reflux for 2 hours. The reaction mixture was concentrated to dryness. The
resulting pale yellow solid was slurried in 1% aqueous sodium carbonate solution (250
o.
Part A
PartC
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mL), collected by vacuum filtration, and air-dried on the funnel overnight to provide 25 g
of 1 -(7-bromo-l#-imidazo[4,5-c]qu^
PartD
A 1 -liter round bottom flask was charged with l-(7-bromo-l//-imidazo[4,5-
5 c]quinolin-l-yl)-2-methylpropan-2-ol (25.0 g, 78.0 mmol), dichloromethane (400 mL) and
chloroform (100 mL). To this solution was slowly added in small portions 3-
chloroperoxybenxzoic acid (34.0 g of 60 % purity, 1 17 mmol, 1.5 eq). The reaction was
maintained at room temperature for 2 hours and then concentrated ammonium hydroxide
solution (200 mL) was added. The mixture was vigorously stirred as /?-toluenesulfonyl
10 chloride (22.4 g, 1 17 mmol) was slowly added in small portions. The reaction was
complete within 1 hour but was left to stir at room temperature overnight. The reaction
mixture was filtered to collect a pale yellow solid. The product was purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30%
CMA in chloroform). The resulting pale yellow solid was slurried in cold acetonitrile,
1 5 isolated by filtration, and air-dried on the vacuum filter to provide 1 7.2 g of 1 -(4-amino-7-
bromo-liy-imidazo[4,5-c]quinolin-l-yl)-2-methylpropan-2-ol. The filtrate was transferred
to a separatory funnel and the layers were separated. The aqueous layer was extracted
with chloroform (3 x 100 mL). The chloroform fractions were combined, washed with
brine (100 mL), dried over magnesium sulfate and concentrated to dryness to provide an
20 additional 0.8 g of 1 -(4-amino-7-bromo- l#-imidazo[4,5-c]quinolin- 1 -yl)-2-methylpropan-
2-ol,mp>250°C.
MS(ESI) m/z 335, m/z 337 (M+H) + ;
Anal. Calcd. for Ci 4 Hi 5 BrN 4 0: C, 50.17; H, 4.51; N, 16.71. Found: C, 49.96; H, 4.44; N,
16.75.
25 PartE
A thick walled glass reaction vessel was charged with anhydrous DMF (2 mL),
palladium (II) acetate (34 mg, 0.15 mmol, 0.005 eq), tri-otolylphosphine (91 mg, 0.3
mmol, 0.01 eq) and triethylamine (12.4 ml, 89.4 mmol, 3 eq). To this orange solution was
added a solution of l-(4-amino-7-bromo-l/f-imidazo[4,5-c]quinolin-l-yl)-2-
30 methylpropan-2-ol (10.0 g, 29.8 mmol) in 100 mL anhydrous DMF followed by the
addition of methyl acrylate (2.82 g, 32.8 mmol, 1.1 eq). The reaction mixture was purged
with nitrogen, sealed and heated at 120 °C overnight. The heat was turned off and the dark
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orange reaction mixture was slowly cooled to room temperature. The reaction mixture
was poured into a solution of water (600 mL), saturated aqueous potassium carbonate (200
mL) and saturated aqueous sodium chloride 100 mL). An orange precipitate crashed out
of solution. The solid was collected by vacuum filtration to provide 7.9 g of product. A
small amount of product was purified by chromatography using a HORIZON HPFC
system (silica cartridge, eluting with 20% methanol in dichloromethane:dichloromethane
in a gradient from 1-15% over 300 mL, 15-40% over 1700 mL, and 40% for 1000 mL).
The resulting material was recrystallized from 75:25 acetonitrile/methanol and dried to
provide methyl (2£)-3-[4-amino-l -(2-hydroxy-2-methylpropyl)-li/-imidazo[4,5-
c]quinolin-7-yl]prop-2-enoate 3 mp >250 °C.
MS (APCI) m/z 341 (M+H) + ;
Anal. Calcd. for C 18 H2oN 4 03- 0.5 CH 3 OH: C, 62.35; H, 6.22; N, 15.72. Found: C, 62.24;
H 5 6.26; N, 16.10.
Example 16
Methyl 3-[4-amino-l-(2-hydroxy-2-methylpropyl)-l^-imidazo[4,5-c]quinolin-7-
yl]propanoate
NH,
A Parr vessel was charged 10% palladium on carbon catalyst (3.0 g), and a slurry
of methyl (2£)-3 - [4-amino- 1 -(2-hydroxy-2-methylpropyl)- 1 tf-imidazo [4,5 -c]quinolin-7-
yl]prop-2-enoate (7.5 g, 22.0 mmol) in 1:1 methanol/ethanol solution (200 mL). The
vessel was evacuated and charged with hydrogen gas (50psi, 3.4 x 10 5 Pa). The vessel
was shaken for 3 days. The reaction was not complete. The reaction was charged with
additional catalyst (1 g), placed under hydrogen pressure, and shaken overnight. The
reaction was still not complete. The reaction was placed under hydrogen pressure and
heated at 50 °C overnight. The reaction was now complete. The catalyst was removed by
filtering the reaction mixture through a 0.2 micron PTFE membrane filter. The filtrate was
concentrated to dryness. The residue was purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with a CMA:CHC1 3 gradient: 0-8% over 200 mL,
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3-30% over 3200 mL, and 30% for 2400 mL). The pure fractions were combined and
concentrated to give one lot of product. The impure fractions were combined and
concentrated, and the residue was slurried in acetonitrile, collected by vacuum filtration,
and combined with the first lot to provide 2.7 g of white solid. A small portion of this
material was further purified by chromatography using a HORIZON HPFC system
(eluting with a 20% methanol/dichloromethane in dichloromethane gradient: 0-40% over
2400 mL). The pure fractions were combined, concentrated under reduced pressure,
recrystallized from acetonitrile, filtered, and dried on the vacuum funnel to provide methyl
3-[4-amino-l-(2-hydroxy-2-methylpropyl)-l//-imidazo[4,5-c]quinolin-7-yl]propanoate as
a white solid, mp 201-205 °C.
MS (ESI) m/z 343 (M+H) + ;
Anal. Calcd. for C8H22N4O3: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.02; H, 6.56; N,
16.37.
Example 17
Methyl (2i^-3-[4-amino-2-e%l-l-(2-h^^
c]quinolin-7-yl]prop-2-enoate
A thick walled glass reaction vessel was charged with anhydrous DMF (2 mL),
palladium (II) acetate (19 mg, 0.085 mmol, 0.005 eq), tri-o-tolylphosphine (51 mg, 0.17
mmol, 0.01 eq) and triethylamine (7.25 g, 52.02 mmol, 3 eq). To this orange solution was
added a solution of l-(4-amino-7-bromo-2-ethyl-l//-imidazo[4,5-c]quinolin-l-yl)-2-
methylpropan-2-ol (U.S. Patent Application Publication No. US 2004/0147543 Example
142-144, 6.3 g, 17.34 mmol) in 100 mL anhydrous DMF followed by methyl acrylate
(1 .64 g, 19.08 mmol, 1 . 1 eq). The reaction mixture was purged with nitrogen, sealed and
heated to 120 °C overnight. The heat was turned off and the dark orange reaction mixture
was slowly cooled to room temperature. The reaction mixture was poured into a solution
of water (600 mL), saturated aqueous potassium carbonate (200 mL) and saturated
aqueous sodium chloride (100 mL). The mixture was transferred to a separatory funnel
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and extracted with chloroform. The chloroform fractions were combined and concentrated
to dryness. The product was purified by chromatography using a HORIZON HPFC
system (silica cartridge, eluting with a CMA: chloroform gradient: 0-5 % over 200 mL, 5-
30% over 3200 mL, and then 30% for 2400 mL) to provide approximately 4 g of product.
A small portion was further purified by chromatography using a HORIZON HPFC system
(silica cartridge, eluting with a 20% methanol/dichloromethane in dichloromethane
gradient: 0-10% over 200 mL, 10-40% over 1650 mL, and then 40% for 500 mL) followed
by recrystallization from acetonitrile/methanol to provide methyl (2£)-3-[4-amino-2-ethyl-
1 -(2-hydroxy-2-methylpropyl)- 1 tf-imidazo [4,5 ~c]quinolin-7-yl]prop-2-enoate, mp 23 8-
240 °C.
MS (ESI) m/z 369 (M+H) + ;
Anal. Calcd. for C20H24N4O3* 1.0 CH 3 OH: C, 62.99; H, 7.05; N, 14.00. Found: C, 63.00;
H, 7.12; N, 13.67.
Example 18
Methyl (2^-3-[4-amino-l-(2-hydroxy-2-methylpropyl)-li/-imidazo[4,5-c]quinolin-8-
yl]prop-2-enoate
I
Part A
A 2-liter round bottom flask was charged with l-(4-amino-l//-imidazo[4,5-
c]quinolin-l-yl)-2-methylpropan-2-ol (50.0 g, 0.195 mol.) and DMF (1 L). To this stirred
suspension was added a solution of N-bromosuccinimide (41.7 g, 0.234 mol, 1.2 eq) in
DMF (200 mL). The reaction was stirred at ambient temperature overnight. The dark red
solution was poured into 2% aqueous potassium carbonate solution (8 L). After 30
minutes the resulting mixture was filtered through a layer of CELITE filter agent followed
by a rinse of 4 L of deionized water and 1 L of DMF. The aqueous filtrate was divided
into five 2.5 L fractions and each was extracted with chloroform (3 x 600 mL), diluted
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with DMF (200 mL), and extracted again with chloroform (3 x 600 mL). The combined
organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness.
After drying overnight under high vacuum, a reddish brown solid remained (50 g). This
material was slurried in concentrated sodium bisulfite (200 mL) for 30 minutes and then
5 filtered, rinsed with water, and dried on vacuum funnel overnight to provide 50 g of
product. A small sample was purified by chromatography using a HORIZON HPFC
system (silica cartridge, eluting with a gradient of chloroform/CMA; 0-8% over 200 mL,
8-20% over 2000 mL, 20-30% over 1000 mL, 30% over 2400 mL) followed by trituration
with hot acetonitrile. The resulting bright yellow solid was further purified by
10 chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient
of 20% methanol/dichloromethane in dichloromethane: 0-10 % over 200 mL, 10-40%
over 2400 mL, and 40% over 1200 mL) followed by recrystallization from
acetonitrile/methanol to provide 0.65 g of l-(4-amino-8-bromo-l#-imidazo[4,5-
c]quinoIin-l-yl)-2-methylpropan-2-ol as an off-white solid, mp 197-198 °C.
15 MS (APCI) m/z 335, 337 (M+H) + ;
Anal. Calcd. for Ci4Hi 5 BrN 4 0: C, 50.17; H, 4.51; N, 16.71 . Found: C, 50.24; H, 4.57; N,
16.62.
PartB
The method described in Example 15 Part E can be used to couple l-(4-amino-8-
20 bromo-l//-imidazo[4,5-c]quinolin-l-yl)-2-methylpropan-2-ol with methyl acrylate to
provide methyl (2£)-3-[4-amino- 1 -(2-hydroxy-2-methylpropyl)- 1 #-imidazo[4 5 5-
c]quinolin-8-yl]prop-2-enoate.
Examples 19-24
25 A solution of 7-bromo-2-ethoxymethyl-l-(3-isopropoxypropyl)-l//-imidazo[4,5-
c]quinolin-4-amine (42 mg, 0.1 mmol, Example 1 Parts A - D) in 1,4-dioxane (1 mL) was
added to a test tube containing copper iodide (8 mg), potassium phosphate (42 mg), and a
reagent (0. 12 mmol) from the table below and the tube was purged with nitrogen. Trans-
1 ,2-diaminocyclohexane (7 |iL) was added to the tube. The tube was purged with nitrogen
30 and then heated with stirring in a sand bath at 1 1 0 °C for about 6 days. The reaction
mixture was filtered and the filtrate was concentrated by vacuum centrifiigation. The
compounds were purified by preparative high performance liquid chromatography (prep
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HPLC) using a Waters FractionLynx automated purification system. The prep HPLC
fractions were analyzed using a Waters LC/TOF-MS, and the appropriate fractions were
centrifuge evaporated to provide the trifluoroacetate salt of the desired compound.
Reversed phase preparative liquid chromatography was performed with non-linear
gradient elution from 5-95% B where A is 0.05% trifluoroacetic acid/water and B is
0.05% trifluoroacetic acid/acetonitrile. Fractions were collected by mass-selective
triggering. The table below shows the reagent used for each example, the structure of the
resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
? H 2 CH 3
H 3 C^ CH 3
Example
Reagent
R 3
Measured
Mass (M+H)
19
Methyl Carbamate
O
H 3 C 0 A N^
H
416.2328
20
Methanesulfonamide
H 3 C|
H
436.2006
21
3-Methylbutanamide
CH 3 O
H
442.2820
22
(S)-(+)-2,2-
Dimethylcyclopropanecarboxamide
CH, 1
454.2854
23
3 ,4-Difluorobenzamide
498.2300
24
Benzenesulfonamide
498.2155
Examples 25 and 26
A solution of N- [4-(4-amino-7-bromo-2-ethoxymethyl- 1 /Mmidazo [4,5 -c]quinolin-
yl)butyl]methanesulfonamide (50 mg, 0.1 mmol, U.S. Patent Application Publication No.
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US2004/0147543, examples 612-642) in 1,4-dioxane (1 mL) was added to a test tube
containing copper iodide (19 mg), potassium phosphate (16 mg), and a reagent (0.2 mmol)
from the table below and the tube was purged with nitrogen. TransA ,2-
diaminocyclohexane (18 was added to the tube. The tube was purged with nitrogen,
capped, and then heated with stirring in a sand bath at 1 10 °C for about 16 hours. The
reaction mixture was filtered and the filtrate was concentrated by vacuum centrifugation.
The compounds were purified using the method described in Examples 19-24. The table
below shows the reagent used for each example, the structure of the resulting compound,
and the observed accurate mass for the isolated trifluoroacetate salt.
y H 2 CH 3
n q 3
Example
Reagent
R 3
Measured Mass
(M+H)
25
Cyclopropanecarboxamide
475.2153
26
1,1-Dimethylurea
HN^
CH 3
478.2241
Examples 27-41
A solution of l-{3-[4-amino-8-(2-aminoethyl)-2-(2-methoxyethyl>l/i-
imidazo[4,5-c]quinolin-l-yl]propyl}pyrrolidin-2-one (41 mg, 0.16 mmol, 1.0 eq) in a
mixture of A^N-dimethylacetamide (1 mL) and N,A^diisopropylethylamine (34 \xL) was
added to a test tube containing a reagent from the table below (1.1 eq). The tube was
vortexed overnight at ambient temperature and then the reaction was quenched with water
(100 \xL). The solvent was removed by vacuum centrifugation and the compound was
purified using the method described in Examples 19-24. The table below shows the
reagent used for each example, the structure of the resulting compound, and the observed
accurate mass for the isolated trifluoroacetate salt.
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II
1 1
1 2
s--N /—O
T *s /
N
R ,NH
P
Example
Reagent
R
Measured Mass
(M+H)
27
Acetyl chloride
H 'V
0
453.2643
28
Cyclopropanecarbonyl
chloride
0 '
A
479.2805
29
T^obutvrvl chloride
Y
H 3 C CH 3
481.2954
30
Benzoyl chloride
515.2795
31
Nicotinoyl chloride
hydrochloride
516.2712
32
Methanesulfonyl
chloride
3 0
/loo OOCK
33
Tsonronvl sulfonvl
chloride
H 3 C^CH 3
517.2607
?
N
H 3 C "CH 3
34
Dimethylsulfamoyl
chloride
518.2574
35
Benzenesulfonyl
chloride
6
551.2482
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36
1 J\/Tpt1wlirniHfl , 7nl<*-4-
sulfonyl chloride
1
^— N.
CH 3
555.2527
37
Methyl isocyanate
V
H 3 C' NH
468.2766
38
Isopropyl isocyanate
V
3 ^
CH 3
496.3044
39
Phenyl isocyanate
V
u
530.2836
40
4-
Morpholinylcarbonyl
chloride
V
0
524.3011
41
4-MethyM-
Piperazinecarbonyl
chloride
V
0
N
CH 3
537.3329
Examples 42 - 78
A solution of l-[4-amino-7-(3-aminopropyl)-2-(methoxymethyl)-l/f-imidazo[4,5-
c]quinolin-l-yl]-2-methylpropan-2-ol (35 mg 5 0.1 mmol, 1.0 eq) in a mixture of
chloroform (1 mL), N,N-dimethylacetamide (about 80 nL), and N,N~
diisopropylethylamine (36 ixL) was added to a test tube containing a reagent from the table
below (1 . 1 eq). The tube was vortexed overnight at ambient temperature and then the
reaction was quenched with water (50 jiL). The solvent was removed by vacuum
centrifugation and the compound was purified using the method described in Examples 19
- 24. The table below shows the reagent used for each example, the structure of the
resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
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Example
Reagent
R
Measured Mass
(M+H)
42
Propionyl chloride
r
H,C
414.2485
43
Cyclopropanecarbonyl
chloride
426.2527
44
Butyryl chloride
CH,
428.2683
45
Isobutyryl chloride
r.
H,C CH
428.2637
46
O
Cyclopentanecarbonyl
chloride
454.2795
47
48
Cyclohexanecarbonyl
chloride
Dimethylaminoacetyl
chloride hydrochloride
CH,
468.2937
443.2772
49
3-Methoxybenzoyl
chloride
O
CH
492.2614
95
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50
3-Chlorobenzoyl chloride
CI
496.2090
51
4-Chlorobenzoyl chloride
CI
496.2094
52
Methanesulfonyl chloride
3 0
436.1988
53
Ethanesulfonvl chloride
1
H 3 C
450.2188
54
1 -Propanesulfonyl
chloride
1
CH 3
464.2343
55
Isopropylsulfonyl
chloride
0,9/
s
H 3 C^CH 3
464.2345
56
Dimethylsulfamoyl
chloride
T
H 3 C' N XH 3
465.2298
57
1-Butanesulfonyl
chloride
H 3 C
478.2488
58
Trifluoromethanesulfonyl
chloride
°-|-
490.1765
59
1 -Methylimidazole-4-
sulfonyl chloride
•6
ch 3
502.2260
96
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60
2,2,2-
Trifluoroethanesulfonyl
chloride
504.1884
61
3-
Methoxybenzenesulfonyl
chloride
CH
6
3
528.2272
62
3 -Chlorobenzenesulfony 1
chloride
CI"
6
532.1821
63
4-Chlorobenzenesulfonyl
chloride
c
C
CI
532.1793
64
3 -Pyridine sulfonyl
chloride hydrochloride
/I DO 1 1
to
ivieinyi lsocyonaie
H 3
V
C .NH
415.2461
66
Ethyl isocyanate
V
CH 3
429.2572
67
Isopropyl isocyanate
H 3 C
V
CH 3
443.2747
68
w-Propyl isocyanate
V
NH
H 3 C J
443.2764
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69
Phenyl isocyanate
V
U
477.2596
70
Cyclohexyl isocyanate
V
483.3073
71
3-Methoxyphenyl
isocyanate
V
H 3 C°
3
507.2736
72
4-Methoxyphenyl
isocyanate
V
507.2714
73
3-Chlorophenyl
isocyanate
V
Qr NH
T
CI
511.2195
1A
/4
4-Chlorophenyl
isocyanate
V
511.2211
75
1 -Pyrrolidinecarbonyl
chloride
V
o
455.2779
76
1 -Piperidinecarbonyl
chloride
V
469.2917
77
4-Morpholinylcarbonyl
chloride
V
0
471.2733
98
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78
4-Methyl-l-
piperazinecarbonyl
chloride
V
0
N
CH,
484.2990
Examples 79 - 95
A solution of 3-[4-amino4-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)
imidazo[4,5-c]quinolin-7~yl]propanoic acid (20 mg, 0.1 mmol, 1 eq) in 1:1
methanol :dichloromethane (2 mL) was placed in a test tube. The solvent was removed by
vacuum centrifugation. A solution of 1-hydroxybenzotriazole (29 mg) in pyridine (1 mL)
was added to the tube. The tube was sonicated for 15 minutes to provide a uniform
suspension. A solution of ^-(S-dimethylaminopropyO-A^-ethylcarbodiimide (350 mg) in
pyridine (100 nL) was added to the tube and the mixture was stirred for about 30 minutes.
A reagent (2 eq) from the table below was added, the reaction mixture was stirred at
ambient temperature overnight, and then the reaction was quenched with water (100 \xL).
The solvent was removed by vacuum centrifugation and the compound was purified using
the method described in Examples 19-24. The table below shows the reagent used for
each example, the structure of the resulting compound, and the observed accurate mass for
the isolated trifluoroacetate salt.
NH,
N
VN 0-CH 3
An
OH 3
jO
R
Example
Reagent
R
Measured Mass
(M+H)
79
Isopropylamine
1
H 3 cyNH
CH 3
414.2520
80
Cyclopentylamine
cr
440.2655
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O 1
81
Piperidine
1
O
82
(tf>3-
Hydroxypyrrolidine
6
OH
442.2455
83
3 -Methoxy propylamine
1
1
H 3 C°
444.2607
84
2-Methylpiperidine
1
454.2857
85
Tetrahydrofurfurylamine
1
.NH
456.2646
86
3 , 5 -Dimethy lpiperidine
H 3 C^^XH 3
468.2977
87
Thiophene-2-ethylamine
1
is
482.2198
88
Nipecotamide
1
o
483.2740
89
1-Acetylpiperazine
6
O^CH,
483.2754
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90
4-Piperidineethanol
?
OH
484.2943
91
U-
Dioxidotetrahydrothien-
3-ylamine
490.2134
i
92
1 -(3 - Aminopropyl)-2-
\ Mr ST J J
pyrrolidinone
r
Ann 00C7
497.280/
1
93
Methyl isonipecotate
o^o
CH 3
498.2765
94
1 -Adamantanamine
<> Ah
506.3137
95
Ethyl 2-amino-4-
thiazoleacetate
1
S^NH
H 3 C
541.2277
Example 96
2-(4-Amino4 -isobutyl- ^
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OH
Part A
8-Bromo4-isobutyl-l//-imidazo[4,5-c]quinolin-4-amine (22.0 g, 68.9 mmol),
triethylamine (19.20 mL, 137.8 mmol), dichloro[l,l'-
5 bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (1 .00 g, 1 .37 mmol), and
potassium vinyltrifluoroborate (10.15 g, 75.81 mmol) were dissolved in n-propanol (20
mL/g). The amber colored solution was heated at reflux temperature for 1 8 hours and then
cooled to ambient temperature. The reaction was concentrated under reduced pressure.
The resulting solid was slurried in 1% aqueous sodium carbonate and a fine powder was
10 collected by filtration. The powder was sequentially washed with acetonitrile (5 mL/g) and
10% sodium hydroxide (500 mL). A final purification using a HORIZON HPFC system
(silica cartridge, eluting with 4% methanol/dichloromethane) provided 10 g of 1-isobutyl-
8-vinyl-l//-imidazo[4,5-c]quinolin-4-amine as an off-white solid, MS (APCI) tn/z 267 (M
+ H) + .
15 PartB
A 500 mL round bottom flask was charged with l-isobutyl-8-vinyl-l/f-
imidazo[4,5-c]quinolin-4-amine (850 mg, 3.2 mmol) and 200 mL of tetrahydrofuran. The
flask was purged with nitrogen. A solution of 9-borabicyclo[3.3.1]nonane (0.5M in ,
tetrahydrofuran, 8.5 mL, 4.25 mmol) was added in one portion and the reaction was stirred
20 overnight. Additional 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 12.5 mL, 6.25
mmol) was added and the mixture was stirred for approximately 24 hours. The reaction
was cooled to 0 °C with an ice/water bath and 30% H 2 0 2 (2 mL) was added dropwise.
After 5 minutes, 10% NaOH (5mL) was added dropwise. The reaction was stirred for 30
minutes, diluted with water (100 mL) and then extracted with chloroform (3x lOOmL).
25 The combined organic fractions were concentrated under reduced pressure and purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient
of 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide
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580 rag of 2-(4-amino-l-isobutyl-l//-imidazo[4,5-c]quinolin-8-yl)ethanol as an off-white
solid, mp 214-216 °C.
'H NMR (500 MHz, DMSO-cfc) 8 8.15 (s, 1H), 7.82 (m, 1H), 7.54 (d, J= 8.4 Hz, 1H),
7.31 (dd, J= 8.4, 1.4 Hz, 1H), 6.47 (br s, 2H), 4.68 (t, 7= 5.2 Hz, 1H), 4.39 (d, J= 7.3 Hz,
2H), 3.71-3.68 (m, 2H), 2.87 (t, J= 7.0 Hz, 2H), 2.18 (septet, 7= 6.8 Hz, 1H), 0.93 J= 6.6
Hz,6H);
I3 CNMR(125 MHz, DMSO-rf tf )S 151.5, 143.3, 143.0, 132.1, 131.4, 128.1, 128.0, 125.8,
1 19.9, 1 14.5, 62.2, 53.3, 38.8, 28.3, 19.1;
MS (ESI)w/z285(M + H) + ;
Anal. Calcd. for CeHzoW: C, 67.58; H, 7.09; N, 19.70. Found: C, 67.51; H, 7.36; N,
19.74.
Example 97
3-[4-Amino-l-(2-hydroxy-2-methylpropyl)-l/f-imidazo[4,5-c]quinolin-7-yl]-l-
(morpholin-4-y l)propan- 1 -one
Methyl 3-[4-amino-l-(2-hydroxy-2-methylpropyl)-l//-imidazo[4,5-c]quinolin-7-
yfjpropanoate (2.3 g, 6.7 mmol) was stirred in Claisen's alkali (50 mL) for 30 minutes.
The solution was concentrated under reduced pressure. The resulting white solid was
dissolved in water (200 mL) and washed with chloroform (4x 50 mL). Citric acid was
added to the aqueous fraction until the pH was 5-6. A fine white precipitate formed that
was obtained by filtration to provide 2.5 g of wet 3-[4-amino-l-(2-hydroxy-2-
methylpropyl)-l//-imidazo[4,5-c]quinolin-7-yl]propanoic acid as a white solid. MS (ESI)
m/z329(M + H) + .
PartB
3-[4-Amino-l-(2-hydroxy-2-memylpropyl)-liy-imidazo[4,5-c]quinolin-7-yl]
propanoic acid (500 mg, 1.5 mmol), anhydrous A^AT-dimethylformamide (25 mL), and 1-
Part A
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hydroxybenzotriazole (250 mg, 1.8 mmol) were combined and the reaction was stirred for
15 minutes. l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8 mmol) was
added and the reaction mixture was stirred for an additional 30 minutes. Morpholine (400
mg, 2.3 mmol) was added to the reaction slurry. After five hours 1 -hydroxybenzotriazole
(250 mg, 1.8 mmol), l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8
mmol), and morpholine (400 mg, 2.3 mmol) were added and the mixture was heated at 70
°C for 2 hours. After cooling to ambient temperature, the solvent was removed under
reduced pressure and the residue was partitioned between chloroform (100 ml) and 1%
aqueous sodium carbonate (50 mL). The fractions were separated and organic fraction
was washed 1% aqueous sodium carbonate (2x 50 mL). The combined aqueous fractions
were back extracted with chloroform (50 mL). The combined organic fractions were dried
(MgS0 4 ), filtered, and concentrated under reduced pressure. The resulting off-white solid
was purified by chromatography using a HORIZON HPFC system (silica cartridge,
eluting with a CMA: chloroform gradient; 0-5% CMA over 75 mL, 5-35% over 1500 mL,
and 35% for 600 mL) followed by recrystallization from acetonitrile to provide 335 mg of
3-[4-ammo-l-(2-hydroxy-2-me%lpropyl)-l/f-imidazo[4,5-c]quinolin-7-yl]-l-
(morpholin-4-yl)propan-l-one as an off-white solid, mp 217-218 °C.
! H NMR (500 MHz, DMSO-<f tf ) 8 8.20 (d, J= 8.4 Hz, 1H), 8.03 (s, 1H), 7.45 (d, J= 1.3
Hz, 1H), 7.10 (dd, /= 8.4, 1.5 Hz, 1H), 6.50 (br s, 2H), 4.83 (s, 1H), 4.51 (s, 2H), 3.51-
3.40 (m, 8H), 2.92 (m, 2H), 2.69 (m, 2H), 1.16 (s, 6H);
MS (APCI) m/z 398 (M + H) + ;
Anal. Calcd. for C21H27N5O3: C, 63.46; H, 6.85; N, 17.62. Found: C, 63.29; H, 6.97; N,
17.83.
Example 98
3-[4-Amino-2-ethyl- 1 -(2-hydroxy-2-methylpropyl)-l/f-imidazo[4,5-c]quinolin-7-yl]- 1 -
(morpholin-4-yl)propan- 1 -one
NH,
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3-[4-Amino-2-ethyl4-(2-hydroxy-2-methylpropyl)-l//-imidazo[4,5-c]quinolin-7-
yl]propanoic acid (500 mg, 1.4 mmol), chloroform (100 mL) and 1 -hydroxybenzotriazole
(575 mg, 4.26 mmol) were combined and then stirred for 30 minutes. l-(3-
Dimethylaminopropyl)-3-ethylcarbodiimide (1.00 g, 5.2 mmol) was added and the
reaction was stirred for 30 minutes. Morpholine (lOmL) was added in one portion. After 4
hours, 1% aqueous sodium carbonate (100 mL) was added and the mixture was stirred.
The fractions were separated and the organic fraction was sequentially washed with 1%
aqueous sodium carbonate (50 mL), dried (MgS0 4 ), filtered, and concentrated to a white
solid. Recrystallization from acetonitrile provided 225 mg of 3-[4-amino-2-ethyl-l-(2-
hydroxy-2-methyl-propyl)-lif-imidazo[4,5-c]quinolin-7-yl]- 1 -(morpholin-4-yl)propan-l -
one as a white solid, mp 237-239 °C.
J H NMR (500 MHz, DMSO-4j) 5 8.14 (d, J= 8.5 Hz, 1H), 7.42 (d, J= 1.5 Hz, 1H), 7.08
(dd, J= 8.5, 1.7 Hz, 1H), 6.30 (br s, 2H), 4.76 (s, 1H), 4.51 (br s, 2H), 3.51-3.40 (m, 8H),
3.04 (quartet, J= 7.4 Hz, 2H), 2.91 (m, 2H), 2.68 (m, 2H), 1.34 (t, /= 7.4 Hz, 3H), 1.16
(br s, 6H);
MS (APCI) m/z 426 (M + H) + ;
Anal. Calcd. for C23H31N5O3: C, 64.92; H, 7.34; N, 16.46. Found: C, 64.93; H, 7.31; N,
16.60.
l-{4-Amino-7-[2-(methylsulfonyl)ethyl])-l^-imidazo[4,5-c]quinolin-l-yl}-2-
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (15 mg, 0.07 mmol), acetonitrile (50 mL), methyl vinyl sulfone (268 mg, 2.52
mmol), triethylamine (1.00 mL, 7.17 mmol), tri-o-tolylphosphine (45 mg, 0.21 mmol) and
l-(4-amino-7-bromo-l/f-imidazo[4,5-c]quinolin-l-yl)-2-methylpropan-2-ol (800 mg, 2.39
mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated
Example 99
methylpropan-2-ol
Part A
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at 120 °C in an oil bath. The reaction was maintained at 120 °C for 12 hours, cooled to
ambient temperature, and then concentrated under reduced pressure to yield a dark brown
oil. The oil was partitioned between chloroform (75 mL) and a solution comprised of a 1 :1
combination of 10% aqueous potassium carbonate and 10% sodium hydroxide. A
5 precipitate formed. The mixture was filtered and the recovered solid was purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with 20%
methanol in dichloromethane. The filtrate was also concentrated and the residue purified
by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8%
gradient of methanol in dichloromethane). The two lots of purified product were combined
10 to provide 380 mg of l-{4-amino-7-[2-(methylsulfonyl)ethenyl]-l//-imidazo[4,5-
c]quinolin-l-yl}-2-methylpropan-2-ol as a pale yellow solid. MS (APCI) m/z 361 (M +
H) + .
PartB
A glass Parr vessel was charged with 10% palladium on carbon (0.1 g), methanol
15 (50 mL) and l-{4-amino-7-[2-(me%lsmfonyl)emenyl]-lJY-imidazo[4,5-c]quinolin-l-yl}-
2-methylpropan-2-ol (380 mg, 1.05 mmol). The vessel was evacuated and charged with
hydrogen gas (40 psi, 2.8 x 10 5 Pa). The reaction was shaken at 50 °C for approximately
1 8 hours. The reaction was cooled to ambient temperature, filtered, and then concentrated
under reduced pressure. The resulting crude product was purified by chromatography
20 using a HORIZON HPFC system (silica cartridge, eluting with a 0-35% gradient of CMA
in chloroform) followed by recrystallization from acetonitrile to provide 176 mg of l-{4-
amino-7-[2-(methylsulfonyl)ethyl]-l//-imidazo[4,5-c]quinolin- 1 -yl} -2-methylpropan-2-ol
as an off-white solid, mp 269-271 °C.
'H NMR (500 MHz, DMSO-4$) 8 8.25 (d, J= 8.5 Hz, 1H), 8.05 (s, 1H), 7.50 (d, J= 1.5
25 Hz, 1H), 7.15 (dd, J= 8.4, 1.7 Hz, 1H), 6.54 (br s, 2H), 4.83 (s, 1H), 4.52 (s, 2H), 3.52-
3.49 (m, 2H), 3.13-3.10 (m, 2H), 3.00 (s, 3H), 1.16 (s, 6H);
l3 CNMR(125 MHz,DMSO-^)8 152.1, 145.2, 143.8, 136.3, 132.6, 127.1, 125.3, 121.5,
121.1, 113.6, 69.4, 56.1, 54.3, 40.1, 27.7, 27.0;
MS (APCI) m/z 363 (M + H) + ;
30 Anal. Calcd. for C^NAiS-O.SSCHaCN: C, 56.42; H, 6.16; N, 16.13. Found: C, 56.23;
H, 6.17; N, 16.16.
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Example 100
3-[4-Ammo-2-emyl-l-(2-hydroxy-2-memylpropylH^
dimethylpropanamide
5 Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (50 mg, 0.22 mmol), acetonitrile (50 mL), triethylamine (1 .80 mL, 13.0 mmol), tri-
o-tolylphosphine (200 mg, 0.65 mmol), A^N-dimemylacrylamide (511 mg, 5.16 mmol)
and l-(7-bromo-2-ethyl-l//-imidazo[4,5-c]quinolin-l-yl)-2-methylpropan-2-ol (1.50 g,
0 4.30 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and
heated at 120 °C in an oil bath. The reaction was maintained at 120 °C for 1 8 hours and
then cooled to ambient temperature. Upon cooling a precipitate formed that was dissolved
by the addition of methanol and chloroform. The remaining insoluble material was
removed by filtration through a 0.2 micron PTFE membrane filter. The filtrate was
5 concentrated under reduced pressure and purified by chromatography using a HORIZON
HPFC system (silica, eluting with a 0-25% gradient of CMA in chloroform). The resulting
product was washed with 1% aqueous sodium carbonate and filtered to provide 1 .37 g of
3-[2-ethyl-l-(2-hyaVoxy-2-memylpropyl)-lJf-imidazo[4,5-c]quinolin-7-yl]-A r ,A^
dimethylprop-2-enamide as an off-white solid, mp 196-198 °C.
0 'HNMR (500 MHz, DMSO-ffc) 8 9.15 (s, 1H), 8.61 (d,J= 8.9 Hz, 1H), 8.33 (d, J= 1.3
Hz, 1H), 8.00 (dd, J= 8.9, 1.5 Hz, 1H), 7.66 (d, J= 15.4 Hz, 1H), 7.38 (d, J= 15.4 Hz,
1H), 4.81 (s, 1H), 4.64 (br s, 2H), 3.21 (s, 3H), 3.10 (m, 2H), 2.96 (s, 3H), 1.39 (t,J= 7.4
Hz,3H), 1.20 (s, 6H);
MS(ESI)m/z367(M + H) + ;
5 Anal. Calcd. for CziHtfN^'HjO: C, 67.99; H, 7.20; N, 1 5.10. Found: C, 68.00; H, 7.25;
N, 15.22.
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PartB
A glass Parr vessel was charged with 10% palladium on carbon (0.14 g), methanol
(50 mL) and 3-[2-ethyl-l-(2-hydroxy-2-m^^
ArN-dimethylprop-2-enamide (1.20 g, 3.27 mmol). The vessel was evacuated and charged
5 with hydrogen gas (40 psi, 2.8 x 1 0 5 Pa). The reaction was shaken at 50 °C for
approximately 19 hours. After cooling to ambient temperature, the reaction mixture was
filtered and the filtrate concentrated to dryness to provide crude 3-[2-ethyl-l-(2-hydroxy-
2-methylpropyl)-l//-imidazo[4,5-c]qm^ as a white
semi-solid. MS (APCI) m/z 369 (M + H) + .
10 PartC
To a stirring solution of crude 3-[2-ethyM-(2-hydroxy-2-methylpropyl)-l^-
imidazo^S-cjquinolin-T-y^-^-dimethylpropanamide, (1.2 g, 3.3 mmol) in
dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid ( 60% pure, 941 mg, 3.6
mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the
15 reaction was vigorously stirred for 10 minutes. /?-Toluenesulfonyl chloride (690 mg, 3.6
mmol) was then added in one portion and the reaction was stirred for one hour. The
fractions were separated and the aqueous fraction was extracted with chloroform (3x 50
mL). The combined organic fractions were concentrated under reduced pressure.
Purification of the residue by chromatography using a HORIZON HPFC system (silica
20 cartridge, eluting with 0-6% gradient of methanol in dichloromethane) followed by
recrystallization from acetonitrile provided 651 mg of 3-[4-amino-2-ethyM-(2-hydroxy-
2-methylpropyl)-l#-imidazo[4,5-c^ as an off-
white solid, mp 234-237 °C.
, HNMR(500 MHz, DMSO-^) 8 8.14 (d, J= 8.5 Hz, 1H), 7.42 (d,J= 1.6 Hz, 1H), 7.08
25 (dd, J= 8.5, 1.7 Hz, 1H), 6.30 (br s, 2H), 4.76 (s, 1H), 4.51 (br s, 2H), 3.04 (q, 7= 7.4 Hz,
2H), 2.94 (s, 3H), 2.89 (m, 2H), 2.83 (s, 3H), 2.66 (m 3 2H), 1.34 (t, J = 7.4 Hz, 3H), 1.16
(br s, 6H);
,3 CNMR(75MHz,DMSO-^)5 171.2, 155.5, 151.5, 144.9, 139.0, 133.5, 125.6, 125.1,
121.2, 120.8, 113.4, 70.6, 54.4, 36.5, 34.7,33.9, 30.5,27.5,20.3, 12.0;
30 MS (ESI) m/z 384 (M + H) + ;
Anal. Calcd. for C21H29N5O2: C, 65.77; H, 7.62; N, 18.26. Found: C, 65.76; H, 7.67; N,
18.35.
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Example 101
l-{3-[4-Amino-2-(2-methoxyethyl)-8-(3^
imidazo [4,5 -c] quinolin- 1 ~yl]propyl } pyrrolidin-2-one
Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (8 mg, 0.04 mmol), acetonitrile (50 mL), triethylamine (0.9 mL, 5.2 mmol), tri-o-
tolylphosphine (30 mg, 0.10 mmol), 4-acryloylmorpholine (271 mg, 1.91 mmol) and l-{3-
[8-bromo-2-(2-methoxyethyl)- 1 //-imidazo [4,5 -c]quinolin- 1 -yl]propyl}pyrrolidin-2-one
(0.75 g, 1 .7 mmol). The reaction mixture was purged with nitrogen and the tube was
sealed and heated at 120 °C in an oil bath. The reaction was maintained at 120 °C for 15
hours and then cooled to ambient temperature. Upon cooling a precipitate formed that was
dissolved by the addition of methanol and chloroform. The remaining insoluble material
was removed by filtration through a 0.2 micron PTFE membrane filter. The filtrate was
concentrated to dryness and purified by chromatography using a HORIZON HPFC system
(silica cartridge, eluting with a 0-6% gradient of methanol in dichloromethane) to provide
an off-white solid.
A glass Parr vessel was charged with 10% palladium on carbon (0.08 g), methanol
(50 mL) and the solid. The vessel was evacuated and charged with hydrogen gas (40 psi,
2.8 x 10 5 Pa). The mixture was shaken at 50 °C for approximately 19 hours. After
cooling to ambient temperature, the reaction mixture was filtered and the filtrate was
concentrated to dryness to provide crude l-{3-[2-(2-methoxyethyl)-8-(3-morpholin-4-yl-3-
oxopropyl)-l//-imidazo[4,5-c]quinolin-l-yl] propyl }pyrrolidin-2-one as a white semi-
solid. MS (ESI) m/z 494 (M + H) + .
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PartB
To a stirring solution of crude l-{3-[2-(2-methoxyethyl)-8-(3-morpholin-4-yl-3-
oxopropyl)-l//-imidazo[4,5-c]quinolin-l-yl] propyl }pyrrolidin-2-one, (0.85 g) in
dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 500 mg, 1.91
mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the
reaction was vigorously stirred for 10 minutes. /?-Toluenesulfonyl chloride (690 mg, 3.60
mmol) was added in one portion and the mixture was stirred for one hour. The fractions
were separated and aqueous fraction was extracted with chloroform (3x 50 mL). The
combined organic fractions were concentrated under reduced pressure. Purification by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient
of 0-30% CMA in chloroform) followed by recrystallization from acetonitrile provided 75
mg of l-{3-[4-amino-2-(2-methoxye%l^
imidazo[4,5-c]quinolin-l-yl] propyl }pyrrolidin-2-one as a pale yellow solid, mp 168-170
°C.
*H NMR (300 MHz, DMSO-^j) 5 7.84 (s, 1H), 7.53 (d, 7= 8.5 Hz, 1H), 7.32 (dd, J- 8.5,
1.5 Hz, 1H), 6.35 (br s, 2H), 4.53 (m, 2H), 3.81 (t, 7= 6.6 Hz, 2H), 3.50-3.33 (m, 12H),
3.29 (s, 3H), 3.18 (t, J= 6.7 Hz, 2H), 2.98 (m, 2H), 2.72 (m, 2H), 2..23 (m, 2H), 2.05-1.87
(m,4H);
MS (APCI) m/z 509 (M + H) + ;
Anal. Calcd. for C^eNA*: C, 63.76; H, 7.13; N, 16.52. Found: C, 63.55; H, 6.87; N,
16.41.
Example 102
3- {4-Amino-2-(2-methoxyethyl)- 1 -[3 -(2-oxo-pyrrolidin- 1 -yl)propyl]- 1 tf-imidazo [4,5-
c]quinolin-8-yl}-^,//-dimethylpropanamide
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Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (8 mg, 0.04 mmol), acetonitrile (50 mL), triethylamine (0.9 mL, 5.22 mmol), tri-o-
tolylphosphine (30 mg, 0.10 mmol), N,N-dimethylacrylamide (1 89 mg, 1 .91 mmol) and
5 1 - { 3 - [8 -bromo-2 - (2 -methoxy ethyl)- 1 //-imidazo [4,5 -c] quinolin- 1 -y l]propy 1 } pyrrolidin-2-
one (0.75 g, 1.7 mmol). The reaction mixture was purged with nitrogen and the tube was
sealed and heated at 120 °C in an oil bath. The reaction was maintained at 120 °C for 18
hours and then cooled to ambient temperature. Upon cooling a precipitate formed that was
dissolved by the addition of methanol and chloroform. The remaining insoluble material
10 was removed by filtration through a 0.2 micron PTFE membrane filter. The filtrate was
concentrated under reduced pressure and purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with a 0-7% gradient of methanol in
dichloromethane) to provide 660 mg of 3-{2-(2-methoxyethyl)-l-[3-(2-oxopyrrolidin-l-
yl)propyl]-li^imidazo[4,5-c]quinolin-8-yl}-A^-dimethylprop-2-enamide as an off-white
15 solid.
PartB
A glass Parr vessel was charged with 10% palladium on carbon (0.07 g), methanol
(50 mL) and 3-{2-(2-methoxyethyl)-l-[3-(2-oxopyrrolidin-l-yl)propyl]-l//-imidazo[4,5
c]quinolin-8-yl}-iV,A^-dimethylprop-2-enamide (0.66 g, 1.47 mmol). The vessel was
20 evacuated and charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa). The mixture was shaken
at 50 °C for approximately 72 hours. The reaction mixture was cooled to ambient
temperature and filtered. The filtrate was concentrated under reduced pressure to provide
720 mg of crude 3-{2-(2-methoxyethyl)-l-[3-(2-oxopyrrolidin-l-yl)propyl]-l//-
imidazo^jS-cJquinolin-S-ylJ-A^^/V-dimethylpropanamide as a white semi-solid. MS (ESI)
25 w/z452(M + H) + .
PartC
To a stirring solution of 3-{2-(2-methoxyethyl)-l-[3-(2-oxopyrrolidin-l-
yl)propyl]-l//-imidazo[4,5-c]qm (0.66 g) in
dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 423 mg, 1.62
30 mmol). After 1 8 hours concentrated ammonium hydroxide (50 mL) was added and the
reaction was vigorously stirred for 10 minutes. p-Toluenesulfonyl chloride (311 mg, 1.62
mmol) was then added in one portion. The fractions were separated and aqueous fraction
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was extracted with chloroform (3x 50 mL). The combined organic fractions were
concentrated under reduced pressure and purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with a 0-30% gradient of CMA in chloroform). The
resulting product was washed with a 1% aqueous sodium carbonate and then recrystallized
from acetonitrile to provide 75 mg of 3-{4-amino-2-(2-methoxyethyl)-l-[3-(2-
oxopyrrolidin- 1 -y l)propyl]- 1 Zf-imidazo [4,5-c]quinolin-8-yl } -N,A/-dimethylpropanamide as
an off-white solid, mp 184-186 °C.
1 HNMR(300MHz,DMSO-4)5 7.84(d,J= 1.0 Hz, 1H),7.53 (d,J=8.5Hz, 1H), 7.32
(dd, J= 8.5, 1.5 Hz, 1H), 6.35 (br s, 2H), 4.53 (m, 2H), 3.81 (t, J= 6.7 Hz, 2H), 3.42-3.34
(m, 4H), 3.30 (s, 3H), 3.18 (t, 6.7 Hz, 2H), 3.00-2.92 (m, 5H), 2.82 (s, 3H), 2.70 (m,
2H), 2.23 (m, 2H), 2.06-1 .86 (m, 4H);
MS (ESI)/w/z467(M + H) + ;
Anal. Calcd for C25H34N6O3: C, 64.36; H, 7.35; N, 18.01. Found: G, 64.47; H, 7.33; N,
18.11.
Example 103
l-{4-Amino-2-ethyl-7-[3-oxo-3^
1 -yl} -2-methy lpropan-2-ol
NH,
A glass Parr vessel was charged with 10% palladium on carbon (1.0 g), methanol
(75 mL), ethanol (75 mL) and methyl 3-[4-amino-2-ethyl-l-(2-hydroxy-2-methylpropyl)-
l//-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate (approximately 4 g, 10.8 mmol). The
vessel was evacuated and charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa). The mixture
was shaken at 50 °C for approximately 18 hours. The reaction mixture was cooled to
ambient temperature and filtered. The filtrate was concentrated under reduced pressure to
provide 3.55 g of methyl 3-[4-amino-2-ethyl-l-(2-hydroxy-2-methylpropyl)-li/-
imidazo[4,5-c]quinolin-7-yl]propanate as an off-white solid. MS (ESI) m/z 371 (M + H) + .
Part A
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PartB
Methyl 3-[4-amino-2-ethyl-l-(2-hy^
c]quinolin-7-yl]propanate was slurried in Claisen's alkali (50 mL) for 30 minutes and then
concentrated to dryness. The resulting solid was dissolved in water (200 mL) and citric
5 acid was slowly added until the pH reached 5-6. A fine off-white precipitate formed.
Filtration provided 2.83 g of 3-[4-amino-2-ethyl-l-(2-hydroxy-2-methylpropyl)-l/7-
imidazo[4,5-c]quinolin-7-yl]propanoic acid as an off-white solid. MS (ESI) m/z 357 (M +
H) + .
PartC
10 A round bottom flask, equipped with a stir bar, was charged with 3-[4-amino-2-
ethyl- 1 -(2-hydroxy-2-methylpropyl)- 1 #-imidazo[4,5-c]quinolin-7-yl]propanoic acid (5 00
mg, 1.40 mmol), anhydrous pyridine (50 mL) and 1-hydroxybenzotriazole (379 mg, 2.80
mmol). After 30 minutes of stirring l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (537
mg, 2.80 mmol) was added to the reaction mixture in two portions. After 1 5 minutes,
1 5 thiazolidine (250 mg, 2.80 mmol) was added in one portion. The pale yellow solution was
stirred for 1 8 hours and then concentrated under reduced pressure. The resulting foam was
dissolved in dichloromethane and washed with 1% aqueous sodium carbonate (2x 15 mL).
The combined aqueous fractions were extracted with chloroform (3x 30 mL). The
combined organic fractions were purified by chromatography using a HORIZON HPFC
20 system (silica cartridge, eluting with a 0-25% gradient of CMA in chloroform) followed
by recrystallization from acetonitrile to provide 516 mg of l-{4-amino-2-ethyl-7-[3-oxo-3-
(1 ,3-thiazolidin-3-yl)propyl]-l//-imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol as a
white solid, mp 210-212 °C.
^NMR (300 MHz, DMSO-tf*) 8 8.15 (d, J= 8.5 Hz, 1H), 7.44 (d, J= 1.7 Hz, 1H), 7.09
25 (dd, J= 8.5, 1.8 Hz, 1H), 6.35 (br s, 2H), 4.76 (s, 1H), 4.60-4.44 (m, 4H), 3.72-3.63 (m,
2H), 3.08-2.88 (m, 6H), 2.73 (m, 2H), 1.34 (t, J= 7.5 Hz, 3H), 1.17 (br s, 6H);
MS (ESI) m/z 428 (M + H) + ;
Anal. Calcd. for C22H29N5O2S: C, 61.80; H, 6.84; N, 16.38. Found: C, 61.55; H, 6.92; N,
16.50.
30 Example 104
l-{4-Amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)e%l]-lJ7-imidazo[4,5-c]
1 -yl}-2-methylpropan-2-ol
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Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (12 mg, 0.05 mmol), acetonitrile (20 mL), iV,N-dimethylformamide (15 mL)
5 triethylamine (1.10 mL, 7.92 mmol), tri-o-tolylphosphine (48 mg, 0.16 mmol), methyl
vinyl sulfone (294 mg, 2.77 mmol) and 1 -[4-amino-7~bromo-2-(methoxymethyl)- 1 //-
imidazo[4,5-c]quinolin-l-yl)-2-methylpropan-2-ol (1.00 g, 2.64 mmol). The reaction
mixture was purged with nitrogen. The tube was sealed and heated at 120 °C in an oil bath.
The reaction was maintained at 120 °C for 18 hours and then cooled to ambient
10 temperature. The reaction was filtered and the filtrate was concentrated under reduced
pressure. The resulting solid was partitioned between chloroform (100 mL) and aqueous
1% sodium carbonate (100 mL). The fractions were separated and the aqueous fraction
was extracted with chloroform (5x 50 mL). The combined organic fractions were
concentrated and purified by chromatography using a HORIZON HPFC system (silica
15 cartridge, eluting with 0-6% gradient of methanol in dichloromethane) to provide 750 mg
of 1 - {4-amino-2-(methoxymethyl>7-[2-(methy lsulfonyl)ethenyl] - 1 #-imidazo[4,5-
c]quinolin-l-yl}-2-methylpropan-2-ol as a yellow semi-solid. MS (ESI) m/z 405 (M + H) + .
PartB
A glass Parr vessel was charged with 10% palladium on carbon (200 mg),
20 methanol (12.5 mL), ethanol (12.5 mL) and l-{4-amino-2-(methoxymethyl)-7-[2-
(methylsulfonyl)ethenyl]-l//-imidazo[4,5-c]quinolin-l-yl}-2-methylpropan (750 mg,
1.85 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8 x 10 5
Pa). The mixture was shaken at 50 °C for approximately 18 hours and then cooled to
ambient temperature. The reaction mixture was sequentially filtered through a 0.2 micron
25 PTFE membrane filter, concentrated under reduced pressure, and purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-7%
gradient of methanol in dichloromethane) to provide 195 mg of l-{4-amino-2-
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(methoxymethyl)-7-[2-(methy lsulfonyl)ethy 1] - 1 //-imidazo [4,5 -e]quinolin- 1 -yl } -2-
methylpropan-2-ol as a white solid, mp 210-212 °C.
] H NMR (500 MHz, DMSO-*) 5 8.22 (d, J= 8.5 Hz, 1H), 7.51 (d, J= 1.7 Hz, 1H), 7. 15
(dd, J= 8.5, 1.8 Hz, 1H), 6.63 (br s, 2H), 5.20-4.50 (m, 5H), 3.51 (m, 2H), 3.30 (s, 3H),
3.12 (m, 2H), 3.00 (s, 3H), 1.16 (br s, 6H);
13 CNMR(125 MHz, DMSO-d 5 ) 8 151.9, 150.3, 145.2, 136.4, 134.1, 125.8, 125.3, 121.5,
121.1, 113.6, 70.5, 66.5, 57.6, 54.7, 54.2, 40.1, 27.6, 27.5;
MS (APCI) m/z 407 (M + H) + ;
Anal. Calcd. for C^N^S-CHaCN: C, 56.35; H, 6.53; N, 15.56. Found: C, 56.10; H,
6.55; N, 15.56.
Example 105
1 - { 4- Amino-2-(hydroxymethy l)-7- [2-(methy lsulfonyl)ethyl] - 1 //-imidazo [4,5 -
c]quinolin- 1 -y 1} -2-methylpropan-2-ol
A stirring solution of l-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethyl]-
l//-imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol (340 mg, 0.84 mmol) in
dichloromethane (40 mL) was sealed with a septum and purged with nitrogen gas. The
solution was cooled in an ice/water bath and a 1 .0 M solution of boron tribromide in
dichloromethane (4.2 mL) was added via syringe. The resulting mixture was stirred for 18
hours while warming to ambient temperature. The mixture was cooled back to 0 °C in an
ice/water bath and the second portion of boron tribromide (1.0 M, 4.2 mL) was added. The
reaction was stirred for 3 hours while warming to ambient temperature. Methanol (30 mL)
was added and the mixture was concentrated to a purple foam. The foam was dissolved in
10% aqueous hydrochloric acid (30 ml) and washed with chloroform (2x 25 mL). The
aqueous fraction was neutralized by the slow addition of solid potassium carbonate until
the pH reached 1 1 . The aqueous fraction was extracted with chloroform (2x 50 mL) and
allowed to stand overnight. The resulting solid was recovered by filtration to provide 126
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mg of 1 - {4-amino-2-(hydroxymethyl)-7-[2-(methylsulfonyl)ethyl] - 1 #-imidazo [4,5 -
cjquinolin- 1 -yl}-2-methylpropan-2-ol
as a white crystalline solid, mp 221-223 °C.
X U NMR (300 MHz, DMSO-tf*) 8 8.21 (d, J = 8.5 Hz, 1H), 7.49 (d, J= 1 .6 Hz, 1H), 7.14
(dd, J= 8.5, 1.8 Hz, 1H), 6.51 (br s, 2H), 5.48 (br s, 1H), 5.12-4.77 (m, 3H), 4.69 (br s,
2H), 3.51 (m, 2H), 3.11 (m, 2H), 3.00 (s, 3H), 1.17 (br s, 6H);
I3 CNMR(125 MHz, DMSO-d*) 6 153.6, 152.0, 145.3, 136.1, 133.9, 125.7, 125.4, 121.4,
121.0, 1 13.8, 70.5, 56.5, 54.6, 54.3, 40.1, 27.6, 27.5;
MS (APCI) m/z 393 (M + H) + ;
Anal. Calcd. for C^N^S-OJSHzO: C, 53.25; H, 6.33; N, 13.80. Found: C, 53.05; H,
6.51; N, 13.62.
Example 106
3 - [4- Amino-2-(methoxymethy l)-7 -(3 -morpholin-4-y 1 -3 -oxopropy 1)- 1 H-
imidazo [4 , 5 -c] quinolin- 1 -y 1] -2-methylpropan-2-ol
NH 2
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (150 mg, 0.66 mmol), acetonitrile (50 mL), N f iV-dimethylformamide (20 mL)
triethylamine (5.50 mL, 39.54 mmol), tri-o-tolylphosphine (600 mg, 1.98 mmol), methyl
acrylate (294 mg, 2.77 mmol) and l-[4-amino-7-bromo-2-(methoxymethyl)-l//-
imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol (5.00 g, 13.2 mmol). The reaction
mixture was purged with nitrogen and the tube was sealed and heated at 120 °C for 1 8
hours. The reaction was cooled to ambient temperature and then concentrated to dryness
under reduced pressure. The resulting solid was partitioned between chloroform (300 mL)
and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the
aqueous fraction was extracted with chloroform (4x 100 mL). The combined organic
fractions were concentrated and purified by chromatography using a HORIZON HPFC
Part A
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system (silica cartridge, eluting with 0-8% gradient of methanol in dichloromethane) to
provide a yellow semi-solid.
The intermediate product was added to a Parr vessel with 10% palladium on
carbon (700 mg), methanol (12.5 mL), and ethanol (12.5 mL). The vessel was evacuated
5 and charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa). The mixture was shaken at 50 °C
for approximately 18 hours followed by cooling to ambient temperature. The mixture was
filtered through a 0.2 micron PTFE membrane filter and the filtrate was concentrated
under reduced pressure to provide crude methyl 3-[4-amino-l -^-hydroxy^-
methylpropyl^^methoxymethyl)-!^^ as a white
1 0 solid. MS (APCI) m/z 387 (M + H) + .
PartB
Methyl 3- [4-amino- 1 -(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)- 1 H-
imidazo[4,5-c]quinolin-7-yl]propanoate was slurried in Claisen's alkali (50 mL) for 30
minutes and then concentrated to dryness. The resulting solid was dissolved in water (200
1 5 mL) and citric acid was slowly added until the pH reached 5-6. A fine off-white
precipitate formed. Filtration provided 7.58 g of wet 3-[4-amino-l-(2-hydroxy-2-
methylpropyl)-2-(methoxymethyl)-l^-imidazo[4 5 5-c]quinolin-7-yl]propanoic acid as a
white solid. MS (APCI) m/z 373 (M + H) + .
PartC
20 3-[4-Anruno-l-(2-hydroxy-2-meth^
c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-
hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred
for 30 minutes. l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was
added and the reaction mixture was stirred for an additional 15 minutes. Morpholine (581
25 mg, 6.60 mmol) was added in one portion. After stirring for 1 8 hours the solution was
concentrated under reduced pressure. The resulting foam was dissolved in chloroform (50
mL) and washed with 1% aqueous sodium carbonate (2x 15 mL). The combined aqueous
washes were extracted with chloroform. The combined organic fractions were
concentrated under reduced pressure and then purified by chromatography using a
30 HORIZON HPFC system (silica cartridge, eluting with a CMA: chloroform gradient; 0-
20% CMA over 1500 mL, followed by 20-25% CMA over 500 mL, and finally 25-30%
CMA over 500 mL). A final recrystallization from acetonitrile provided 913 mg of 3-[4-
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amino-2-(methoxymeth^
l-yl]-2-methylpropan-2-ol as an off-white solid, mp 215-217 °C.
! H NMR (500 MHz, DMSO-4?) 5 8.15 (d, ./= 8.5 Hz, 1H), 7.45 (d, J= 1.6 Hz, 1H), 7.1 1
(dd, J= 8.5, 1.8 Hz, 1H), 6.55 (br s, 2H), 5.15-4.50 (br s, 2H), 4.89 (s, 1H), 4.63 (br s,
2H), 3.51-3.39 (m, 8H), 3.30 (s, 3H), 2.92 (t, J= 7.6 Hz, 2H), 2.69 (t, J= 7.6 Hz, 2H),
1.16 (brs, 6H);
MS (ESI)/w/z442 (M + H) + ;
Anal. Calcd. for C23H31N5O4: C, 62.57; H, 7.08; N, 15.86. Found: C, 62.42; H, 6.90; N,
15.92.
Example 107
1 - [4-Amino-7-[3 -(1,1 -dioxidothiomorpholin-4-y l)-3 -oxopropyl]-2-(methoxymethyl)- 1
imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol
NH,
3-[4-Amino- 1 -(2-hydroxy-2-methy lpropy l)-2-(methoxymethyl)- 1 #-imidazo[4,5-
c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-
hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred
for 30 minutes. l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was
added and the reaction mixture was stirred for an additional 15 minutes. Thiomorpholine
1,1-dioxide (895 mg, 6.60 mmol) was added in one portion. After stirring for 1 8 hours the
solution was concentrated under reduced pressure and the residual foam was dissolved in
chloroform (50 mL) and washed with 1% aqueous sodium carbonate (2x 25 mL). The
combined aqueous washes were extracted with chloroform. The combined organic
fractions were concentrated under reduced pressure and purified by chromatography using
a HORIZON HPFC system (silica cartridge, eluting with a CMA: chloroform gradient; 0-
25% CMA over 1500 mL, followed by 25-30% CMA over 500 mL, finally 30% CMA
over 1000 mL). The resulting material was subjected to a second chromatography
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purification using a HORIZON HPFC system (silica cartridge, eluting with CMA:
chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 500
mL) followed by recrystallization from acetonitrile to provide 1.07 g of l-[4-amino-7-[3-
(1,1 -dioxidothiomorpholin-4-yl)-3-oxopropyl]-2-(methoxymethyl)- 1 #-imidazo[4,5-
5 c]quinolin-l~yl]-2-methylpropan-2-ol as a white solid, mp 190-192 °C.
! H NMR (500 MHz, DMSO-*) 5 8.16 (d, J= 8.5 Hz, 1H), 7.46 (d, J= 1.4 Hz, 1H), 7.1 1
(dd, J= 8.5, 1.6 Hz, 1H), 6.53 (br s, 2H), 5.14-4.50 (br s, 2H), 4.88 (s, 1H), 4.64 (br s,
2H), 3.90-3.83 (m, 4H), 3.30 (s, 3H), 3.13 (m, 2H), 3.07 (m, 2H), 2.93 (t, /= 7.5 Hz, 2H),
2.81 (t, J= 7.5 Hz, 2H), 1.16 (br s, 6H);
1 0 MS (ESI) in/z 490 (M + H) + ;
Anal. Calcd. for C23H31N5O5S: C, 56.43; H, 6.38; N, 14.30. Found: C, 56.44; H, 6.33; N,
14.29.
Example 108
3-[4-Amino-l-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-l//-imidazo[4,5-
1 5 c]quinolin-7-yl]-.¥^/-dimethylpropanamide
3-[4-Amino-l-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-li/-imidazo[4,5-
c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-
hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred
20 for 30 minutes. l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was
added and the reaction mixture was stirred for an additional 1 5 minutes. Dimethylamine
hydrochloride (540 mg, 6.60 mmol) was added in one portion and the reaction was stirred
for an additional 4 hours. The solution was concentrated under reduced pressure and the
resulting oil was dissolved in chloroform (50 mL) and washed with 1% aqueous sodium
25 carbonate (3x 25 mL). The combined aqueous washes were extracted with chloroform.
The combined organic fractions were purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with a CMA: chloroform gradient; 0-25% CMA
over 1500 mL, followed by 25-30% CMA over 1000 mL) followed by recrystallization
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from acetonitrile to provide 931 mg of 3-[4-amino-l-(2-hydroxy-2-methylpropyl)^
(methoxymethyl)-l#~im^ as a white
solid, mp 142-145 °C.
] H NMR (500 MHz, DMSO-tf d ) 8 8,16 (d, J= 8.5 Hz, 1H), 7.45 (d, J= 1.7 Hz, 1H), 7.1 1
(dd, J= 8.5, 1.7 Hz, 1H), 6.56 (br s, 2H), 5.1 1-4.52 (br s, 2H), 4.89 (s, 1H), 4.64 (br s,
2H), 3.30 (s, 3H) 5 2.94 (s, 3H), 2.91 (t, J= 7.7 Hz, 2H), 2.83 (s, 3H), 2.67 (t, J= 7.7 Hz,
2H), 1.17 (brs, 6H);
13 CNMR(125 MHz, DMSO-d*) 5 171.2, 151.9, 150.0, 145.4, 139.7, 134.1, 125.6, 125.1,
121.4, 121.0, 113.2, 70.5, 66.6, 57.5, 54.7, 36.5, 34.7, 33.9, 30.5, 27.5;
MS (APCI) rn/z 400 (M + H) + ;
Anal. Calcd. for C^NsCVO.SHzO: C, 61.75; H, 7.40; N, 17.14. Found: C, 61.74; H,
7.47; N, 17.25.
Example 109
N- {3-[4- Amino- 1 -(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)- 1 H-
imidazo[4,5-c]quinolin-7-yl]propyl}methanesulfonamide
NH 9
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (225 mg, 1.00 mmol), acetonitrile (50 mL) 3 N, iV-dimethylformamide (20 mL)
triethylamine (8.25 mL, 59.3 mmol), tri-o-tolylphosphine (900 mg, 2.97 mmol),
acrylonitrile (770 mg, 21.8 mmol) and l-[4-amino-7-bromo-2-(methoxymethyl)-l//-
imidazo[4,5-c]quinolin-l-yl)-2-methylpropan-2-ol (7.50 g, 19.8 mmol). The reaction
mixture was purged with nitrogen and the tube was sealed and heated at 120 °C in an oil
bath for 18 hours. The reaction was cooled to ambient temperature and then concentrated
under reduced pressure. The resulting solid was partitioned between chloroform (300 mL)
and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the
aqueous fraction was extracted with chloroform (4x 100 mL). The combined organic
fractions were concentrated under reduced pressure and purified by chromatography using
Part A
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a HORIZON HPFC system (silica cartridge, eluting with 0-7% gradient of methanol in
dichloromethane) to provide 5.2 g of 3-[4-amino-l-(2-hydroxy-2-methylpropyl)-2-
(methoxymethyl)-l/^imidazo[4 5 5-c]quinolin-7-yl]prop-2-enenitrile as an off-white solid.
MS (ESI)m/z352(M + H) + .
5 PartB
A glass Parr vessel was charged with 10% palladium on carbon (1.0 g), methanol
(200 mL), trifluoroacetic acid (5.4 mL, 72.5 mmol) and 3-[4-amino-l-(2-hydroxy-2-
me%lpropyl)-2-(methoxymethyl)-ltf-im^ (5.1
g, 14.5 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8 x 10 5
10 Pa). The mixture was shaken for approximately 1 8 hours and then filtered through a 0.2
micron PTFE membrane filter and concentrated under reduced pressure. The resulting
yellow oil was dissolved in 10% aqueous hydrochloric acid (100 mL) and stirred for 30
minutes. The solution was made basic (pH 10) by the slow addition of potassium
carbonate. Potassium hydroxide was added until pH equaled 13. The solution was then
1 5 concentrated under reduced pressure. The resulting off-white solid was slurried in hot
methanol (300 mL) and filtered. The hot methanol slurry procedure was repeated. The
combined filtrates were concentrated and purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with a CMA: chloroform gradient; 0-30% CMA) to
provide 4.7 g of l-[4-amino-7-(3-aminopropyl)-2-(methoxymethyl)-l//-imidazo[4,5-
20 c]quinolin-l-yl]-2-methylpropan-2-ol as an off-white foam. MS (APCI) mfz 358 (M + H) + .
PartC
To a solution of l-[4-amino-7-(3-aminopropyl)-2-(methoxymethyl)-l//-
imidazo[4 5 5-c]quinolin-l-yl]-2-methylpropan-2-ol (1.25 g, 3.50 mmol) and triethylamine
(2.4 mL, 17.5 mmol) cooled to 0 °C in a ice water bath was added methanesulfonic
25 anhydride (732 mg, 4.20 mmol). The solution was stirred for approximately 18 hours
while warming to ambient temperature. The solution was concentrated under reduced
pressure and partitioned between 1% aqueous sodium carbonate (125 mL) and chloroform
(100 mL). The aqueous fraction was extracted with chloroform until no product was
present in the aqueous layer. The combined organic fractions were concentrated and
30 purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting
with a CMA: chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30%
CMA over 1000 mL). A final recrystallization from acetonitrile provided 855 mg of AT-{3-
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[4-amino-l-(2-hydroxy-2-me%lpropyl)-2<methoxymethyl)4^midazo[4,5-c]quinolin-
7-yl]propyl}methanesulfonamide as a white solid, mp 205-207 °C.
! H NMR (500 MHz, DMSO-rf*) 8 8.17 (d,J= 8.5 Hz, 1H), 7.42 (d, J= 1 .7 Hz, 1H), 7.09
(dd, J= 8.5, 1.7 Hz, 1H), 7.05 (t, J= 5.6 Hz, 1H), 6.52 (br s, 2H), 5.1 1-4.57 (br s, 2H),
4.88 (s, 1H), 4.64 (br s, 2H), 3.30 (s, 3H), 2.99 m, 2H), 2.89 (s, 3H), 2.72 (t, J= 7.6 Hz,
2H), 1.83 (m, 2H), 1.17 (br s, 6H);
MS (APCI) m/z 435 (M + H) + ;
Anal. Calcd. for C 2 oH29N504S'0.25H 2 0: C, 54.59; H, 6.75; N, 15.91. Found: C, 54.47; H,
6.73; N, 16.20.
3-[4-Amino-l-(2-hydroxy-2-methylpropyl)-2-(methoxyme%l)-l//-imidazo[4,5-
A glass Parr vessel was charged with 10% palladium on carbon catalyst (200 mg),
methanol (100 mL), and 3-[4-amino-l-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-
l/j r -imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile (925 mg, 2.63 mmol). The vessel was
evacuated and charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa). The mixture was shaken
at 50 °C for approximately 18 hours. The reaction mixture was cooled to ambient
temperature and then filtered through a 0.2 micron PTFE membrane filter. The filtrate was
concentrated under reduced pressure and purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with a CMA: chloroform gradient; 0-25% CMA
over 1500 mL, followed by 25-30% CMA over 500 mL) to provide 760 mg of 3-[4-
amino-l-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-m-imidazo[4,5-c]quinolin-7-
yl]propanenitrile as a white solid, mp 191-193 °C.
*H NMR (500 MHz, DMSO-</ 6 ) 6 8.22 (d, J= 8.5 Hz, 1H), 7.52 (d, J= 1.7 Hz, 1H), 7.14
(dd, J= 8.5, 1.7 Hz, 1H), 6.62 (br s, 2H), 5.1 1-4.57 (br s, 2H), 4.89 (s, 1H), 4.65 (br s,
2H), 3.30 (s, 3H), 2.99 (t, J= 7.0 Hz, 2H), 2.89 (t, J= 7.0 Hz, 2H), 1.17 (br s, 6H);
Example 110
c]quinolin-7-yl]propanenitrile
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!3 CNMR(125 MHz, DMSO-dfc) 8 152.0, 150.2, 145.3, 137.0, 134.0, 125.8, 125.4, 121.4,
121.0, 120.3, 113.8, 70.5, 66.6, 57.5, 54.7, 30.4, 27.5, 17.9;
MS (APCI) rn/z 354 (M + H) + ;
Anal. Calcd. for C l9 H 2 3N 5 (V1.0 CH 3 CN: C, 63.94; H, 6.64; N, 21.31. Found: C, 63.66;
H, 6.79; N, 21.12.
3-[4-Amino-2-(hydroxymethyl> 1 -(2-hydroxy-2-methylpropyl)- 1 #-imidazo[4,5-
A stirring solution of S^-amino^-P-hydroxy^-methylpropyl^-
tmethoxymethylHtf-imidazo^S-c^^ (523 mg,
1.31 mmol) in dichloromethane (125 mL) was sealed with a septum and purged with
nitrogen gas. The solution was cooled in an ice/water bath and a 1 .0 M solution of boron
tribromide in dichloromethane (6.6 mL) was added via syringe. The resulting mixture was
stirred for 18 hours while warming to ambient temperature. Methanol (50 mL) was added
and the mixture was concentrated under reduced pressure. The resulting solid was
dissolved in a 2.0 M solution of ammonia in methanol (75 mL) and the solution was
concentrated under reduced pressure to yield a solid. This step was repeated two more
times with silica gel (1 tbsp) being added prior to the final concentration. The sample
absorbed on silica was purified by chromatography using a HORIZON HPFC system
(silica cartridge, eluting with a CMA: chloroform gradient; 0-25% CMA over 1200 mL,
followed by 25-40% CMA over 1300 mL) to provide 298 mg of 3-[4-Amino-2-
(hydroxymethyl)-H2-hydroxy-2-me%^
dimethylpropanamide as a white crystalline solid, mp 228-230 °C.
] H NMR (300 MHz, DMSO-^) 8 8.15 (d, J= 8.5 Hz, 1H), 7.42 (d, J= 1.6 Hz, 1H), 7.10
(dd, J= 8.5, 1.7 Hz, 1H), 6.43 (br s, 2H), 5.47 (t, J= 5.9 Hz, 1H), 4.95 (s, 1H), 4.86 (br s,
2H), 4.68 (br s, 2H), 2.94 (s, 3H), 2.90 (m, 2H), 2.83 (s, 3H), 2.67 (m, 2H), 1.17 (br s,
Example 1 1 1
c]quinolin-7-yl]-A^^-dimethylpropanamide
NH,
6H);
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MS (ESI)/n/z386(M + H) + ;
Anal. Calcd. for CjoHzyNsOs-O^O: C, 60.90; H 3 7.16; N, 17.75. Found: C, 60.93; H,
7.42; N, 17.85.
5 H4-Amino-2-(hydroxym^
cjquinolin- 1 -yl]-2-methylpropan-2-ol
A stirring solution of l-[4-amino-2-(methoxymethyl)~7-(3-morpholin-4--yl--3--
oxopropyl)-li/-imidazo[4 5 5-c]quinolin-l-yl]-2-methylpropan-2^ (460 mg, 1.04 mmol) in
10 chloroform (120 mL) was sealed with a septum and purged with nitrogen gas. The
solution was cooled in an ice water bath and a solution of 1 .0 M boron tribromide in
dichloromethane (6.6 mL) was added via syringe. The reaction was stirred for 18 hours
while warming to ambient temperature. In order to complete the reaction three additional
portions (3 mL, 10 mL, and 10 mL) of 1.0 M boron tribromide in dichloromethane were
1 5 added at approximately 1 8 hour intervals. Methanol (75 mL) was added. The reaction was
concentrated to a dark purple liquid and then stirried in 10% aqueous hydrochloric acid
(100 mL) for three days. Solid sodium carbonate was slowly added until the pH equaled
1 0. The solution was concentrated to a white solid. The solid was washed with methanol
(2x 100 mL) and filtered. The filtrate was absorbed onto silica (2 tbsp) and then purified
20 by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a
CMA: chloroform gradient; 0-20% CMA over 1400 mL, followed by 20-30% CMA over
1600 mL) to provide 48 mg of l-[4-amino-2-(hydroxymethyl)-7-(3-morpholin-4-yl-3-
oxopropyl)- 1 #-imidazo [4,5 -c]quinolin- 1 -yl]-2-methylpropan-2-ol
as a white crystalline solid, mp 223-225 °C.
25 ! H NMR (500 MHz, DMSO-^) 8 8.15 (d, J= 8.5 Hz, 1H), 7.43 (d, 7 = 1.3 Hz, 1H), 7.10
(dd, J= 8.5, 1 .5 Hz, 1H), 6.44 (br s, 2H), 5.47 (t, J= 5.8 Hz, 1H), 4.96 (s, 1H), 4.87 (br s,
Example 112
NH
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2H), 4.68 (br s, 2H), 3.52-3.48 (m, 2H), 3.45-3.38 (m, 6H), 2.92 (t, J = 7.6 Hz, 2H), 2.69
(t, J= 7.7 Hz, 2H), 1.17 (br s, 6H);
MS (ESI) ;«/z 428 (M + H) + ;
Anal. Calcd. for C^^NjO^ C, 61.81; H, 6.84; N, 16.38. Found: C, 61.62; H, 6.77; N,
5 16.26.
Example 113
3-[4-Amino- 1 -(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)- l#-imidazo[4,5-
c]quinolin-7-yl]propanamide
O OH
10 3-[4-Amino-l-(2-hydroxy-2-m
c]quinolin-7-yl]propanenitrile (430, mg, 1.30 mmol) in methanol (75 mL) was heated to 50
°C in an oil bath. Aqueous 10% sodium hydroxide (0.33 mmol) and 30% aqueous
hydrogen peroxide (516 mg, 4.55 mmol) were added and the reaction was stirred for 18
hours. The mixture was cooled to ambient temperature and then concentrated under
1 5 reduced pressure. The resulting solid was slurried in water (70 mL). The aqueous mixture
was washed with chloroform (35 mL), concentrated to a wet solid, slurried in methanol
(100 mL) and filtered. The filtrate was absorbed onto silica (1 tbsp) and purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with CMA:
chloroform gradient; 0-20% CMA over 1400 mL, followed by 20-25% CMA over 1200
20 mL). The material was further purified by chromatography using a HORIZON HPFC
system (silica cartridge, eluting with a 0-9% gradient of methanol in dichloromethane) to
provide 102 mg of 3-[4-amino-l-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-l//-
imidazo[4,5-c]quinolin-7-yl]propanamide as a white solid, mp 228-230 °C.
! H NMR (500 MHz, DMSO-^) 5 8.15 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 1.3 Hz, 1H), 7.32
25 (s, 1H), 7.07 (dd, J= 8.4, 1.4 Hz, 1H), 6.77 (s, 1H), 6.49 (br s, 2H), 5.1 1-4.63 (br s, 2H),
4.87 (s, 1H), 4.63 (br s, 2H), 3.30 (s, 3H), 2.90 (t, J= 7.7 Hz, 2H), 2.43 (t, J= 7.7 Hz, 2H),
1,16 (brs, 6H);
MS (ESI) m/z 372 (M + H) + ;
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Anal Calcd. for C19H25N5O3: C, 61.44; H, 6.78; N, 18.85. Found: C, 61.27; H, 6.64; N,
18.74.
Example 114
l-[4-Amino-7-[3-(l,l-dioxidothiom
5 imidazo[4,5-c]quinolin-l -yl]-2-methylpropan-2-ol
To a stirring solution of l-[4-amino-7-[3-(l,l-dioxidothiomorpto
oxopropyl]-2-(methoxymethy0
(655 mg, 1.34 mmol) in dichloromethane (125 mL), sealed with a septum and purged with
10 nitrogen gas, was added a 1.0 M solution of boron tribromide in dichloromethane (6.6 mL)
via syringe. The resulting mixture was stirred for 18 hours. Methanol (50 mL) was added
and the solution was concentrated under reduced pressure. The resulting solid was
dissolved in a 2.0 M solution of ammonia in methanol (75 mL) and then concentrated
under reduced pressure to a solid. This step was repeated two more times with silica gel (1
1 5 tbsp) being added prior to the final concentration. The crude product absorbed on silica
was purified by chromatography using a HORIZON HPFC system (silica cartridge,
eluting with a CMA: chloroform gradient; 0-25% CMA over 1200 mL, followed by 25-
40% CMA over 1300 mL). The recovered solid was washed with 1% aqueous sodium
carbonate and filtered to provide 325 mg of l-[4-amino-7-[3-(l,l-dioxidothiomorpholin-4-
20 yl)-3-oxopropyl]-2-(hydroxymethylH
ol as an off white semi-solid.
l U NMR (500 MHz, DMSO-tf*) 5 8.16 (d, J= 8.5 Hz, 1H), 7.45 (d, J= 1.4 Hz, 1H), 7.1 1
(dd, J= 8.5, 1.6 Hz, 1H), 6.46 (br s, 2H), 5.48 (br s, 1H), 4.97 (s, 1H), 4.87 (br s, 2H), 4.68
(br s, 2H), 3.91-3.82 (m, 4H), 3.13 (m, 2H), 3.07 (m, 2H), 2.93 (t, J= 7.7 Hz, 2H), 2.81 (t,
25 J= 7.7 Hz, 2H), 1.17 (br s, 6H);
MS (ESI) m/z476(M + H) + ;
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Anal. Calcd. for C 2 2H29N 5 O 5 S*0.5H2O: C, 54.23; H, 6.24; N, 14.45. Found: C, 54.17; H,
6.14; N, 14.68.
N- { 3-[4-Amino-l -(2-hydroxy-2-methylpropyl)-2-(methoxymethy 1)- 1 //-imidazo [4,5 -
c]quinolin-7-yl]propyl) acetamide
c]quinolin-l-yl]-2-methylpropan-2-ol (1 .25 g, 3.50 mmol) in triethylamine (2.4 mL, 17.5
mmol) was cooled to 0 °C in an ice water bath and acetic anhydride (393 mg 3 3.85 mmol)
was added. The solution was stirred for approximately 18 hours while warming to ambient
temperature. The solution was concentrated under reduced pressure and the residue was
partitioned between 1% aqueous sodium carbonate (125 mL) and chloroform (50 mL).
Successive chloroform extractions were performed until no product was present in the
aqueous layer. The combined organic fractions were concentrated under reduced pressure
and dissolved in methanol (100 mL). To this solution was added solid potassium carbonate
(3 tsp) and the reaction was heated to reflux temperature for 2 hours. After cooling to
ambient temperature, the mixture was filtered, concentrated and partitioned between water -
(50 mL) and chloroform (50 mL). Crude product was extracted from the aqueous fraction
through successive chloroform extractions until no product remained in the aqueous layer.
The combined organic extracts were concentrated and purified by chromatography using a
HORIZON HPFC system (silica cartridge, eluting with a CMA: chloroform gradient; 0-
30% CMA over 1500 mL, followed by 30% CMA over 1000 mL) to provide 578 mg of
{3-[4-amino- H2-hydroxy-2-me%^
c]quinolin-7-yl]propyl} acetamide as a white semi-solid.
'H NMR (500 MHz, DMSO-*) 5 8.17 (d, J= 8.5 Hz, 1H), 7.86 (t, J= 5.1Hz, 1H), 7.42 (d,
J= 1.5 Hz, 1H), 7.07 (dd, J= 8.4, 1.6 Hz, 1H), 6.53 (br s, 2H), 5.08-4.57 (br s, 2H), 4.88
(s, 1H), 4.64 (br s, 2H), 3.30 (s, 3H), 3.08 (m, 2H), 2.68 (t, J= 7.6 Hz, 2H), 1 .81 (s, 3H),
1.77 (m, 2H), 1.17 (brs, 6H);
Example 115
NH 2
A solution of 144-amino-7-(3-aminopropyl)-2-(methoxymethyl)-l//-imidazo[4,5-
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MS (APCI) rn/z 400 (M + H) + ;
Anal. Calcd. for Czi^NsOa'O.S^O: C, 61.64; H, 7.41; N, 17.11. Found: C, 61.63; H,
7.13; N, 17.31.
A43-[4-Ajiiino-2-(hydroxy^^
c]quinolin-7-yl]propy 1 } methanesulfonamide
A solution of A^{3-[4-amino-l-(2-hydroxy-2-metty^
l#-imidazo[4,5-c]quinolm^ (630 mg, 1.45 mmol) in
dichloromethane (125 mL) was sealed with a septum and purged with nitrogen gas. A 1 .0
M solution of boron tribromide in dichloromethane (7.3 mL) was added via syringe. The
resulting mixture was stirred for 18 hours. Methanol (50 mL) was added and the solution
was concentrated under reduced pressure. The resulting solid was dissolved in a 2.0 M
solution of ammonia in methanol (75 mL) and then concentrated under reduced pressure.
This step was repeated two more times with silica gel (1 tbsp) being added prior to final
concentration. The crude product absorbed on silica was purified by chromatography
using a HORIZON HPFC system (silica cartridge, eluting with CMA: chloroform
gradient; 0-25% CMA over 1200 mL, followed by 25-40% CMA over 1900 mL). The
solid product was washed with water, filtered, and dried to provide 325 mg of N-{3-[4-
amino-2-(hydroxymethy 1> 1 -(2-hydroxy-2-methylpropyl)- 1 #-imidazo[4,5 -c]quinolin-7-
yljpropyl} methanesulfonamide as a white solid, mp 202-205 °C.
! H NMR (500 MHz, DMSO-^) 5 8.18 (d, /= 8.5 Hz, 1H), 7.42 (d, J= 1.6 Hz, 1H), 7.09
(dd, J= 8.5, 1.7 Hz, 1H), 7.05 (t 5 J= 5.4 Hz, 1H), 6.57 (br s, 2H), 5.51 (br s, 1H), 4.97 (s,
1H), 4.87 (br s, 2H), 4.68 (br s, 2H), 3.00 (m, 2H), 2.89 (s, 3H), 2.72 (t, J= 7.2 Hz, 2H),
1.84 (m, 2H), 1.17 (br s, 6H);
MS (APCI) m/z42\ (M + H) + ;
Anal. Calcd. for C19H27N5O4S: C, 54.14; H, 6.46; N, 16.61. Found: C, 54.10; H, 6.30; N,
Example 116
NH,
16.66.
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Example 117
A44-Amino-2-(ethoxym^
c]quinolin-8-yl]-2-methylpropanamide
Part A
Phosphorous oxychloride (5.45 mL, 58.5 mmol) was added to a slurry of 6-bromo-3-
nitroquinolin-4-ol (15 g, 55.7 mmol) ini\r,iV-dimethylformamide (100 mL). The reaction
mixture was heated to 100 °C for 10 minutes and then cooled to ambient temperature. The
solution was poured into ice water (400 mL) and stirred for 20 minutes. The resulting
precipitate was filtered, washed with water, and dried. The recovered solid was transferred
to a round bottomed flask and tetrahydrofuran (100 mL) was added. A solution of
triethylamine (1 1.6 mL, 83.5 mmol) and l-amino-2-methylpropan-2-ol (5.21 g, 58.5
mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction was stirred for 16
hours. The mixture was poured into water and stirred for 15 minutes. The resulting
yellow solid was filtered and dried to provide 17.2 g of H(6-bromo-3-nitroquinolin-4-
yl)amino]-2-methylpropan~2-ol as a yellow solid.
PartB
l-[(6-Bromo-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol (17.2 g, 50.5
mmol), toluene (150 mL) and isopropanol (20 mL) were added to a Parr flask containing
5% platinum on carbon (1.7 g) wetted with toluene. The flask was evacuated three times,
charged with hydrogen to 30 psi, and shaken for 72 hours. The reaction mixture was f
filtered through a pad of CELITE filter agent. The CELITE was washed with several
portions of dichloromethane followed by methanol. The filtrate was concentrated to
provide crude l-[(3-amino-6-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol as a brown
oil.
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PartC
Ethoxyacetyl chloride (6.2 g, 50.5 mmol) was added dropwise to a solution of
crude 1 -[(3-amino-6-bromoquinolin^-yl)amino]-2-methylpropan-2-ol, dichloromethane
(500 mL), and triethylamine (7 mL, 50.5 mmol). After stirring for 16 hours, water was
added and the mixture was stirred for an additional 2 hours. The fractions were separated.
The organic fraction was washed with water, concentrated under reduced pressure and
redissolved in ethanol (500 mL). Water (150 mL) and potassium carbonate (10.5 g) were
added and the mixture was heated at reflux temperature for 3 hours. The ethanol was
removed under reduced pressure. The remaining aqueous fraction was extracted with
ethyl acetate (2 x 500 mL). The organic fractions were combined, washed with water
followed by saturated aqueous sodium chloride, dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile
provided 10.4 g of l-[8-bromo-2-(ethoxymethyl)-l//-imidazo[4,5-c]quinolin-l-yl]-2-
methylpropan-2-ol as a tan powder.
PartD
l-[8-Bromo-2-(ethoxyme%l)-liW^
ol (0.550 g, 1.45 mmol), isobutyramide (0.150 g, 1.74 mmol), copper(I) iodide (0.055 g,
0.290 mmol), potassium phosphate (0.647 g, 3.05 mmol), and 1,4-dioxane (1.5 mL) were
added to a scintillation vial. l,2-(±)-/rara-Diaminocyclohexane (0.035 mL, 0.290 mmol)
was added. The vial was flushed with nitrogen, sealed with a Teflon-lined cap and heated
at 1 10 °C for 72 hours. The vial was cooled to ambient temperature and the reaction was
diluted with dichloromethane and methanol. Purification by chromatography with a
HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 1-15% CMA
in chloroform) provided 0.38 g of iV-[2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-
l//-imidazo[4,5-c]quinolin-8-yl]-2-methylpropanamide as a dark semi-solid.
PartE
3-Chloroperoxybenzoic acid (60% pure, 0.283 g, L0 mmol) was added to a
solution ofA^^2-(ethoxymethyl)-lK2-hydroxy-2-methylpropyl)-l//-imidazo[4,5^
c]quinolin-8-yl]-2-methylpropanamide (0.380 g, 1.0 mmol) in chloroform (10 mL) and the
reaction was stirred for 1 hour. The mixture was cooled in an ice bath and ammonium
hydroxide (3 mL) was added. After 15 minutes of stirring, p-toluenesulfonyl chloride
(0.190 g, 1 .0 mmol) was added and the reaction mixture was stirred for 72 hours. The
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fractions were separated and the aqueous fraction was extracted with chloroform. The
combined organic fractions were washed with brine and purified by chromatography using
a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-20% CMA
in chloroform). Recrystallization from acetonitrile provided 0.23 1 g of iV-[4-amino-2-
(ethoxymemyl)-l-(2-hydroxy-2-memylpropyl)-l//-imidazo[4,5-c]quinolin-8-yl]-2-
methylpropanamide as an off-white solid, mp 259-261 °C.
'HNMR (300 MHz, DMSO-rf*) 5 9.88 (s, 1H), 8.86 (d, J= 1.7 Hz, 1H), 7.53-7.42 (m,
2H), 6.41 (s, 2H), 5.15-4.73 (m, 2H), 4.90 (s, 1H), 4.63 (s, 2H), 3.51 (q, J= 7.0 Hz, 2H),
2.68-2.59 (m, 1H), 1.22 (br s, 6H), 1.14 (d, J= 6.9 Hz, 6H), 1.13 (t, J= 7.0 Hz, 3H);
MS (ESI) m/z 400.17 (M + H) + ;
Anal. Calcd. for C 2 ,H 29 N 5 0 3 : C, 63.14; H, 7.32; N, 17.53. Found: C, 62.78; H, 7.20; N,
17.48.
Example 118
^{2-[4-Armno-2-ethyl-l-(2-hydroxy-2-memylpropyl)-liy-imidazo[4,5-c]quinolin-7-
yl]ethyl } methanesulfonamide
Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (64 mg, 0.29 mmol), acetonitrile (50 mL), N-vinylphthalimide (1.19 g, 6.89
mmol), triethylamine (2.4 mL, 17 mmol), tri-o-tolylphosphine (260 mg, 0.86 mmol) and
l-(7-bromo-2-ethyl-li/-imidazo[4,5-c]quinolin-l-yl)-2-methylpropan-2-ol (2.00 g, 5.74
mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated
at 120 °C in an oil bath for 16 hours. The reaction was cooled to ambient temperature and
silica gel (20 g) was added followed by concentration under reduced pressure. The sample
absorbed on silica was purified by chromatography using a HORIZON HPFC system
(silica cartridge, eluting with a 0-7% gradient of methanol in dichloromethane). The
recovered solid was washed with 1% aqueous sodium carbonate to provide 1.95 g of 2-{2-
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[2-ethyl-l-(2-hydroxy-2-methylpropyl)4/f-imidazo[4,5-c]quinohn-7-yl]ethenyl}-l/^
isoindole-l,3(2#)-dione as a bright yellow solid. MS (APCI) m/z 441 (M + H) + .
PartB
A glass Parr vessel was charged with 10% palladium on carbon (0.4 g), methanol
(75 mL) and 2-{2-[2-e%l-l-(2-hy±:oxy-2-methylpropyl)-l//-imidazo[4 5 5-c]quinolin-7-
yl]ethenyl}-l#-isoindole-l,3(2#)-dione (1.9 g, 4.3 mmol). The vessel was evacuated and
charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa). The reaction was shaken at 50 °C for
approximately 18 hours and then cooled to ambient temperature. The reaction mixture was
filtered followed by concentration under reduced pressure to provide 1.9 g of 2-{2-[2-
emyl4^2-hydroxy-2-me%lpropyl)4/f4midazo[4,5-c]quinolin-7-yl]emyl}-l^-isoindole-
l,3(2#)-dione as a bright yellow solid. MS (APCI) m/z 443 (M + H) + .
PartC
2- {2-[2-ethyl- 1 -(2-hydroxy-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-
yl]emyl}-ltf-isoindole-l,3(2.£z)-dione (1.90 g, 4.29 mmol) in dichloromethane (75 mL)
was combined with 3-chloroperoxybenzoic acid (60% pure, 1 .24 g, 4.72 mmol) and the
reaction was stirred for 1 8 hours. Concentrated ammonium hydroxide (40 mL) was added
and the mixture was vigorously stirred for an additional 10 minutes. p-Toluenesulfonyl
chloride (900 mg, 4.72 mmol) was added and the mixture was stirred for an additional 1
hour. The fractions were separated and the aqueous fraction was extracted with chloroform
(3x 50 mL). The combined organic fractions were sequentially dried (MgS0 4 ), filtered,
and concentrated under reduced pressure. Purification by chromatography using a
HORIZON HPFC system (silica cartridge, eluting with 0-8% gradient of methanol in
dichloromethane) provided 1.05 g of 2-{2-[4-amino-2-ethyl-l-(2-hydroxy-2-
methylpropyl)- 1 //-imidazo [4,5-c]quinolin-7-yl]ethyl} - 1 /7-isoindole- 1 ,3 (2//)-d ione as an
off-white foam. MS (APCI) m/z 458 (M + H) + .
Part D:
2-{2-[4-amino-2-ethyl-l-(2-hydroxy-2-methylpropyl)-l//-imidazo[4,5-c]quinolin-
7-yl]ethyl}-l//-isoindole-l,3(2//)-dione (1.05 g, 2.29 mmol) was dissolved in 2:1 ethanol:
tetrahydrofuran (100 mL), combined with hydrazine hydrate (150 mg, 2.98 mmol) and
heated to reflux temperature for three hours. Additional hydrazine hydrate (0.25 mL) was
added and solution was refluxed for an additional 18 hours. The reaction mixture was
cooled to ambient temperature and filtered. The crude solid was combined with
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triethylamine (2.1 mL, 153 mmol) in dichloromethane (75 mL) and the solution was
cooled to 0 °C in an ice/water bath. Methanesulfonic anhydride (585 mg, 3.35 mmol) was
added and solution was stirred for approximately 18 hours while warming to ambient
temperature. The solution was concentrated under reduced pressure and the residue was
slurried in 1% aqueous sodium carbonate (125 mL). The aqueous mixture was extracted
with chloroform (50 mL) until no product was present in the aqueous fraction. The
combined organic fractions were sequentially dried (MgS04), filtered, concentrated under
reduced pressure, and purified by chromatography using a HORIZON HPFC system
(silica cartridge, eluting with a CM A: chloroform gradient; 0-25% CMA over 1200 mL,
followed by 25-30% CMA over 1 100 mL). A final recrystallization for acetonitrile
provided 328 mg of A^-{2-[4-amino-2-ethyl-l-(2-hydroxy-2-methylpropyl)-l//-
imidazo[4,5-c]quinolin-7-yl]ethyl}methanesulfonamide as an off-white solid, mp 149-152
°C.
l HNMR (500 MHz, DMSO-^) 5 8.18 (d, /= 8.5 Hz, 1H), 7.45 (d, J= 1.6 Hz, 1H), 7.10
(m, 1H), 7.09 (dd, J= 8.5, 1.7 Hz, 1H), 6.37 (br s, 2H), 4.77 (s, 1H), 4.52 (br s, 2H), 3.26
(m, 2H), 3.04 (q, J = 7.4 Hz, 2H), 2.87 (t, J= 7.4 Hz, 2H), 2.82 (s, 3H), 1 .34 (t, J= 7.5 Hz,
3H), 1.16 (brs, 6H);
MS (APCI) m/z 406 (M + H) + ;
Anal. Calcd. for C19H27N5O3S: C, 56.28; H, 6.71 ; N, 17.27. Found: C, 56.00; H, 6.87; N,
17.44.
Example 119
1 - {3-[4-Amino-8-(2-aminoethyl)-2-(2-methoxyethyl)- 1 #-imidazo[4,5-c]quinolin- 1 -yl]
propyl}pyrrolidin-2-one
NH 2 O
Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (17 mg, 0.08 mmol), acetonitrile (50 mL), N-vinylphthalimide (716 mg, 4.13
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mmol), triethylamine (1.6 mL, 11 mmol), tri-o-tolylphosphine (69 mg, 0.22 mmol) and 1-
{348-bromo-2K2-methoxyethyl)4J^imidazo[4 > 5-c]quinolin-l^
(1 .62 g, 3.76 mmol). The reaction mixture was purged with nitrogen and the tube was
sealed and heated at 120 °C in an oil bath for 15 hours. The reaction was cooled to ambient
5 temperature and methanol (50 mL) and chloroform (50 ml) were added. After filtering
through a 0.2 micron PTFE membrane, the solution was concentrated under reduced
pressure and then purified by chromatography using a HORIZON HPFC system (silica
cartridge, eluting with a 0-8% gradient of methanol in dichloromethane) to provide 2.0 g
of 2-(2- {2-(2-methoxyethyl)4 ^
10 c]quinolin-8-yl}ethenyl)-l//-isoindole-l 5 3(2//)-dione as a bright yellow solid.
MS (APCI) m/z 524 (M + H) + .
PartB
A glass Parr vessel was charged with 10% palladium on carbon (0.2 g), methanol
(75 mL) and 2-(2-{2-(2-methoxyethyl)-l-[3-(2-oxopyrrolidin-l-yl)propyl]-li/-
15 imidazo[4,5-c]quinolm-8-yl}eta (2.0 g, 3.8 mmol). The
vessel was evacuated and charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa). The reaction
was shaken at 50 °C for approximately 18 hours. After cooling to ambient temperature, the
reaction mixture was filtered followed by concentration under reduced pressure to provide
2.1 gof2<2-{2-(2-methoxyethylH^3-(2-oxo^
20 c]quinolin-8-yl}ethyl)-l//-isoindole-l ,3(2/i>dione as a pale yellow solid. MS (ESI) m/z
526(M + H) + .
PartC
2-(2- {2-(2-Methoxyethyl)-l -[3-(2-oxo-pyrrolidin-l -yl)propyl]- 1 j^-imidazo[4,5-
c]quinolin-8-yl}ethyl)-l//-isoindole-l,3(2i : /)-dione (2.1 g, 3.8 mmol) in dichloromethane
25 (75 mL) was combined with 3-chloroperoxybenzoic acid (60% pure, 2.0 g, 7.5 mmol) and
the reaction was stirred for 18 hours. Concentrated ammonium hydroxide (40 mL) was
added and the mixture was vigorously stirred for an additional 10 minutes, p-
Toluenesulfonyl chloride (791 mg, 4.12 mmol) was added and the mixture was stirred for
an additional 1 hour. The fractions were separated and aqueous fraction was extracted with
30 chloroform (lOx 35 mL). The combined organic fractions were sequentially dried
(MgS0 4 ), filtered, and concentrated to provide 2.2 g of 2-(2-{4-amino-2-(2-
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methoxyethyl)-l -[3-(2-oxopyrrolidin-l -yl) propyl]-l tf-imidazo[4,5-c]qumolin-8-
yl}e%l)-l#-isoindole-l,3(2#)dione as an off-white foam. MS (APCI) m/z 541 (M + H) + .
PartD
2-(2- {4-Amino-2-(2-methoxyethyl)- 1 -[3-(2-oxopyrrolidin- 1 -yl) propyl]- 1//-
imidazo[4,5-c]quinolin-8-yl}ethyl)-l/f-isoindole-l,3(2/0dione (2.2 g, 4.1 mmol) was
dissolved in 2:1 ethanol: tetrahydrofuran (40 mL), combined with hydrazine hydrate (410
mg, 8.2 mmol) and heated at reflux temperature for three hours. Additional hydrazine
hydrate (0.25 mL) was added and the solution was refluxed for an additional 1 .5 hours.
The reaction was cooled to ambient temperature, filtered and the filtrate concentrated
under reduce pressure. Purification by chromatography using a HORIZON HPFC system
(silica cartridge, eluting with a 0-40% CMA: chloroform gradient over 3.8 L) provided
650 mg of l-{3-[4-amino-8-(2-aminoethyl)-2-(2-methoxyethyl)-lH-imidazo[4,5-
c]quinolin-l-yl] propyl} pyrrolidin-2-one as an off-white solid. MS (ESI) m/z 41 1 (M +
H) + .
Example 120
2-Ethyl-7-[2-(methylsulfonyl)ethyl])-l-(tetrahydro-2/f-pyran-4-ylmethyl)-l/f-
imidazo[4,5-c]quinolin-4-amine
Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (7 mg, 0.03 mmol), acetonitrile (15 mL), iV^-dimethylformamide (15 mL), methyl
vinyl sulfone (150 mg, 1.41 mmol), triethylamine (0.53 mL, 3.8 mmol), tri-o-
tolylphosphine (23 mg, 0.08 mmol) and 7-bromo-2-ethyl-l-(tetrahydro-27y-pyran-4-
ylmethyl)-lH-imidazo[4,5-c]quinolin-4-amine (500 g, 1.28 mmol). The reaction mixture
was purged with nitrogen and the tube was sealed and heated at 120 °C in an oil bath for
16 hours. The reaction mixture was cooled to ambient temperature and then concentrated
under reduced pressure. The resulting solid was partitioned between chloroform (100 mL)
and 1% aqueous sodium carbonate (100 mL). The fractions were separated and the
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aqueous fraction was extracted with chloroform (2x 50 mL). The combined organic
fractions were sequentially dried (MgS0 4 ), filtered, and purified by chromatography using
a HORIZON HPFC system (silica cartridge, eluting with a CMA: chloroform gradient, 0-
15% CMA over 1200 mL followed by 15-20% CMA over 1 100 mL). Recrystallization
5 from methanol provided 3 1 5 mg of 2-ethyl-7-[2-(methylsulfonyl)ethenyl]- 1 -(tetrahydro-
2i^-pyran-4-ylmethyl)-l/f-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid.
] HNMR (500 MHz, DMSO-40 8 8.08 (d, J= 8.6 Hz, 1H), 7.89 (d, J= 1.8 Hz, 1H), 7.62-
7.53 (m, 3H), 6.65 (br s, 2H), 4.46 (d, /= 7.1 Hz, 2H), 3.82 (m, 2H), 3.15-3.12 (m, 2H),
3.12 (m, 3H), 2.96 (q, J= 7.4 Hz, 2H), 2.07 (m, 1H), 1.51-1.40 (m, 4H), 1.38 (t, J= 7.4
10 Hz,3H);
MS(ESI)ah/z415(M + H) + .
PartB
A glass Parr vessel was charged with 10% palladium on carbon (0.2 g), methanol
(25 mL), ethanol (25 mL) and 2-ethyl-7-[2-(methylsulfonyl)ethenyl]-l-(tetrahydro-2/f-
1 5 pyran-4-ylmethyl)-l//-imidazo[4,5-c]quinolin-4-amine (3 1 5 mg, 0.76 mmol). The vessel
was evacuated and charged with hydrogen gas (40 psi, 2.8 x 10 s Pa). The reaction was
shaken at 50 °C for approximately 1 8 hours and then cooled to ambient temperature. The
reaction mixture was sequentially filtered, concentrated under reduced pressure, and
purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting
20 with CMA: chloroform gradient, 0-1 0% CMA over 1000 mL followed by 1 0-25% CMA
over 1000 mL). A final recrystallization from acetonitrile provided 125 mg of 2-ethyl-7-
[2-(methylsulfonyl)ethyl])- 1 -(tetrahydVo-2#-pyran-4-ylmethyl)-l #-imidazo[4,5 -
c]quinolin-4-amine as a white crystalline solid, mp 246.5-249.0 °C.
l U NMR (500 MHz, DMSO-^) 5 7.97 (d, J= 8.5 Hz, 1H), 7.52 (d, J= 1 .7 Hz, 1H), 7.21
25 (dd,J= 8.4, 1.8 Hz, 1H), 6.48 (br s, 2H), 4.42 (d, J= 7.0 Hz, 2H), 3.83-3.80 (m, 2H),
3.53-3.50 (m, 2H), 3.17-3.11 (m, 4H), 3.02 (s, 3H), 2.94 (q, J= 7.4 Hz, 2H), 2.07 (m, 1H),
1.51-1.40 (m, 4H), 1.37 (t, J= 7.4 Hz, 3H);
13 CNMR(125MHz,DMSO-rf tf )5 154.2, 151.7, 144.9, 136.1, 132.3, 126.2, 125.6, 121.7,
120.2, 113.3, 66.4, 54.3,49.6, 40.1,35.6, 29.5,27.6, 20.0, 11.9;
30 MS(ESI)/n/z417(M + H) + ;
Anal. Calcd. for C21H28N4O3S: C, 60.55; H, 6.78; N, 13.45. Found: C, 60.63; H, 6.70; N,
13.76.
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Example 121
3-[4-Amino-2-ethyl-l-(tetrahyfo^
yl]propanenitrile
Part A
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II)
acetate (225 mg, 1.00 mmol), acetonitrile (15 mL), ^-dimethylformamide (15 mL), .
acrylonitrile (1.20 g, 22.6 mmol), triethylamine (8.6 mL, 62 mmol), tri-o-tolylphosphine
(935 mg, 3.10 mmol) and 7-bromo-2-ethyl-l-(tetrahydro-2/f-pyran-4-ylmethyl)-l//-
imidazo[4,5-c]quinolin-4-amine (8.00 g, 20.5 mmol). The reaction mixture was purged
with nitrogen and the tube was sealed and heated at 120 °C for approximately 18 hours.
The reaction was cooled to ambient temperature and methanol (100 mL) was added. The
reaction was filtered and the filtrate concentrated under reduced pressure. The resulting
solid was washed with 1% aqueous sodium carbonate (100 mL) followed by washing with
water (2x 100 mL). Purification by chromatography using a HORIZON HPFC system
(silica cartridge, eluting with a CMA: chloroform gradient, 0-15% CMA over 1500 mL
followed by 15-25% CMA over 2.4 L) provided 5.2 g of a mixture of cis and trans
isomers of 3-[4-amino-2-ethyl-l -(tetrahydro-2//-pyran-4-ylmethyl)-l/f-imidazo[4,5-
c]quinolin-7-yl]prop-2-enenitrile as a yellow solid. MS (APCI) m/z 362 (M + Hf.
PartB
A glass Parr vessel was charged with 10% palladium on carbon (0.05 g), methanol
(20 mL), and 3-[4-amino-2-ethyl-l-(tetrahydro-2//-pyran-4-ylmethyl)-l/f-imidazo[4,5-
c]quinolin-7-yl]prop-2-enenitrile (100 mg, 0.27 mmol). The vessel was evacuated and
charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa). The reaction was shaken at 50 °C for
approximately 18 hours and then cooled to ambient temperature. The reaction mixture was
sequentially filtered, concentrated under reduced pressure, and purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:
chloroform gradient, 0-30% CMA). A final recrystallization from acetonitrile provided 71
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mg of 3-[4-amino-2-ethyl-l -(tetrahydro-2iy-pyran-4-ylmethyl)-l #-imidazo[4,5-
c]quinolin-7-yl]propanenitrile as a white solid, mp 273-275 °C.
'H NMR (500 MHz, DMSO-40 5 7.97 (d, 7= 8.4 Hz, 1H), 7.53 (d, J= 1.7 Hz, 1H), 7.20
(dd, J= 8.4, 1.8 Hz, 1H), 6.45 (br s, 2H), 4.42 (d, J= 7.2 Hz, 2H), 3.82 (m, 2H), 3.15 (m,
2H), 3.00-2.88 (m, 6H), 2.08 (m, 1H), 1.51-1.40 (m, 4H), 1.37 (t, J= 7.4 Hz, 3H);
,3 CNMR(125 MHz,DMSO-rf tf )5 154.2, 151.7, 144.8, 136.6, 132.3, 126.2, 125.5, 121.6,
120.3, 120.1, 1 13.4, 66.4, 49.6, 35.6, 30.4, 29.5, 20.0, 17.9, 11.9;
MS (ESI) m/z 364 (M + H) + ;
Anal. Calcd. for Ca^sNjO: C, 69.40; H, 6.93; N, 19.27. Found: C, 69.16; H, 6.87; N,
19.25.
Example 122
3-[4-Amino-2-etoyl- 1 -(tetrahydro-2^
yl]propanamide
NH,
3-[4-Arnino-2-ethyl-l-(tetrahydro-2i/-pyran-4-ylmethyl)-l//-imidazo[4,5-
c]quinolin-7-yl]propanenitrile (590 mg, 1.6 mmol), 10% aqueous sodium hydroxide (132
mg, 0.33 mmol), and 30% aqueous hydrogen peroxide (516 mg, 4.55 mmol) were
combined in methanol (75 mL) and the reaction was heated at 50 °C for 1 8 hours. The
mixture was concentrated under reduced pressure and then partitioned between chloroform
(75 mL) and water (75 mL). The fractions were separated and the aqueous fraction was
extracted with chloroform (3x25 mL). The combined organic fractions were sequentially
dried (MgS0 4 ), filtered, concentrated to dryness and purified by chromatography using a
HORIZON HPFC system (silica cartridge, eluting with 2 L of 10% methanol in
dichloromethane). A final recrystallization from acetonitrile provided 35 mg of 3-[4-
ammo-2-etoyl- 1 -(tetrahydro-2#-py^^
yl]propanamide as an off-white solid, mp 197-199 °C.
'H NMR (500 MHz, DMSO-rf tf ) 5 7.92 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 1 .4 Hz, 1H), 7.32
(s, 1H), 7.13 (dd, 7= 8.4, 1.7 Hz, 1H), 6.77 (s, 1H), 6.39 (br s, 2H), 4.40 (d, J= 7.0 Hz,
o
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2H), 3.82 (m 5 2H), 3.15 (m, 2H), 2.95-2.90 (m, 4H), 2.44 (t, J= 7.6 Hz, 2H), 2.08 (m, 1H),
1.51-1.40 (m, 4H), 1.37 (t, J= 7.4 Hz, 3H);
13 CNMR (125 MHz, DMSO-4*) 5 173.3, 154.1, 151.5, 144.8, 139.4, 132.5, 125.9, 125.0,
121.9, 119.8, 112.8, 66.4,49.6, 36.3,35.6, 30.6, 29.5,20.0, 11.9;
5 MS(ESI)/?z/z382(M + H) + ;
Anal. Calcd. for Czi^yNsCVOJO^O: C, 65.20: H, 7.19; N, 18.10. Found: C, 65.19; H,
7.14; N, 18.24.
Example 123
7<3-Aminopropyl)-2-et^
1 0 c]quinolin-4-amine
A glass Parr vessel was charged with 10% palladium on carbon (1 g), methanol (50
mL), 3-[4-amino-2-ethyl- 1 -(tetrahydro-2//-pyran-4-ylmethyl)- 1 tf-imidazo[4,5-c]quinolin-
7-yl]prop-2-enenitrile (4.0 g, 1 1.1 mmol) and trifluoroacetic acid (6.3 g, 55 mmol). The
1 5 vessel was evacuated, charged with hydrogen gas (40 psi, 2.8 x 10 5 Pa) and shaken for
approximately 18 hours. The mixture was filtered and concentrated under reduced
pressure to a yellow oil. The oil was dissolved in 10% aqueous hydrochloric acid and
stirred for 18 hours. Chloroform (100 mL) was added followed by slow addition of
potassium carbonate until the pH equaled 1 1 . The fractions were separated and the
20 aqueous fraction was extracted with chloroform (4x 50 mL). The combined organic
fractions were sequentially dried (MgS0 4 ), filtered, and concentrated under reduced
pressure. Recrystallization from acetonitrile provided 3.55 g of the desired product as a
white solid. A small amount of this material was further purified by chromatography using
a HORIZON HPFC system (silica cartridge, eluting with a CMA: chloroform gradient, 0-
25 30% CMA over 1 000 mL followed by 30% CMA over 1 000 mL). A final recrystallization
from acetonitrile provided 7-(3-aminopropyl)-2-ethyl-l-(tetrahydro-2//-pyran-4-
ylmethyl)-l//-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 217-220 °C.
'HNMR (500 MHz, DMSO-40 5 7.92 (d, J= 8.4 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.12
(dd, J= 8.4, 1.7 Hz, 1H), 6.38 (br s, 2H), 4.40 (d, J= 7.0 Hz, 2H), 3.82 (m, 2H), 3.16 (m,
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2H), 2.93 (q, J= 7.4 Hz, 2H), 2.70 (t, J= 7.6 Hz, 2H), 2.59 (t, 7= 6.8 Hz, 2H), 2.09 (m,
1H), 1.71 (m, 2H), 1.51-1.36 (m, 6H), 1.37 (t, J= 7 A Hz, 3H);
13 CNMR(125 MHz, DMSO-^)S 154.0, 151.5, 144.9, 140.2, 132.5, 125.9, 125.2, 122.0,
119.8, 112.7, 66.4, 49.6,41.2,35.6, 34.9, 32.4, 29.5,20.0, 11.9;
MS (ESI)/h/z368(M + H) + ;
Anal. Calcd. for C 2 iH29N 5 O0.25H 2 0: C, 67.81; H, 7.99; N, 18.83. Found: C, 68.00; H,
8.03; N, 18.75.
Example 124
N-{3-[4-Amino-2-ethyl^
7-y l]propy 1 } methanesulf onamide
NH,
7-(3-Aminopropyl)-2-ethyl- 1 -(tetrahydro-2/f-pyran-4-ylmethyl)-l//-imidazo[4,5-
c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and
methanesulfonic anhydride (260 mg, 1.5 mmol) were combined in dichloromethane (50
mL) at 0 °C and the reaction was stirred for approximately 18 hours. Aqueous sodium
carbonate (1%, 50 mL) was added and the reaction mixture was stirred for one additional
hour. The fractions were separated and the aqueous fraction was extracted with chloroform
(3x 20 mL). The combined organic fractions were sequentially dried (MgS0 4 ), filtered and
purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting
with a CMA: chloroform gradient, 0-20% CMA over 1500 mL followed by 20% CMA
over 500 mL). A final recrystallization from acetonitrile provided 165 mg of 7V-{3-[4-
amino-2-ethyl-l-(tetrahydro-2#-pyran-4-yta^
yl]propyl}methanesulfonamide as a white solid, mp 168-170 °C.
*H NMR (500 MHz, DMSO-^) 5 7.93 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 1.6 Hz, 1H), 7.14
(dd, J= 8.4, 1.7 Hz, 1H), 7.05 (t, J= 5.5 Hz, 1H), 6.40 (br s, 2H), 4.40 (d, J= 7.0 Hz, 2H),
3.82 (m, 2H), 3.16 (m, 2H) 3 3.00 (m, 2H), 2.93 (q, J= 7.4 Hz, 2H), 2.89 (s, 3H), 2.73 (t, J
= 7.6 Hz, 2H), 2.09 (m, 1H), 1.85 (m, 2H), 1.51-1.40 (m, 4H), 1.37 (t, J = 7.4 Hz, 3H);
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13 C NMR (125 MHz, DMSO-rf tf ) 5 154.0, 151.6, 144.9, 139.4, 132.4, 126.0, 125.3, 121.9,
1 19.9, 1 12.8, 66.4, 49.6, 42.0, 39.1, 35.6, 32.1, 31.0, 29.5, 20.0, 1 1.9;
MS (ESI) m/z 446 (M + H) + ;
Anal. Calcd. for C22H31N5O3S: C, 59.30; H, 7.01; N, 15.72. Found: C, 59.22; H, 7.29; N,
15.68.
Example 125
iV-{3-[4-amino-2-ethyl- 1 -(tetrahydro-2i?-pyran-4-ylmethyl)- 1 #-imidazo[4,5-
c]quinolin-7-yl]propyl} acetamide
NH,
7-(3-Aminopropyl)-2-ethyl- 1 -(tetrahydro-2tf-pyran-4-y lmethyl)-l#-imidazo[4,5-
c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and acetic
anhydride (153 mg, 1.5 mmol) were combined in dichloromethane (50 mL) at 0 °C and the
reaction was stirred for approximately 18 hours. Aqueous sodium carbonate (1%, 50 mL)
was added and the reaction mixture was stirred for one additional hour. The fractions were
separated and the aqueous fraction was extracted with chloroform (3x 20 mL). The
combined organic fractions were sequentially dried (MgS0 4 ), filtered and purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:
chloroform gradient, 045% CMA over 2000 mL followed by 15-20% CMA over 500
mL). The desired product was further purified by chromatography using a HORIZON
HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in
dichloromethane). A final recrystallization from acetonitrile provided 142 mg of N-{3-[4-
amino-2-ethyl- 1 -(tetrahydro-2#-pyran-4-ylmethyl)- 1 i/-imidazo[4,5 -c]quinolin-7-
yl]propyl} acetamide as a white solid, mp 209-21 1 °C.
! H NMR (500 MHz, DMSO-40 8 7.92 (d, J= 8.4 Hz, 1H), 7.87 (t, J= 5.1 Hz, 1H), 7.44
(d, J= 1 .5 Hz, 1H), 7.13 (dd, /= 8.4, 1.7 Hz, 1H), 6.39 (br s, 2H), 4.40 (d, J= 7.0 Hz,
2H), 3.82 (m, 2H), 3.16 (m, 2H), 3.09 (m, 2H), 2.93 (q, J= 7.4 Hz, 2H), 2.69 (t, J= 7.6
Hz, 2H), 2.09 (m, 1H), 1.81 (s, 3H), 1.77 (m, 2H), 1.51-1.40 (m, 4H), 1.37 (t, J= 7.4 Hz,
3H);
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,3 CNMR(125 MHz,DMSO-rf tf )8 168.8, 154.0, 151.5, 144.9, 139.6, 132.4, 125.9, 125.3,
121.9, 119.8, 112.8, 66.4, 49.6, 38.1, 35.6, 32.4, 30.6, 29.5, 22.5, 20.0, 11.9;
MS(ESI)m/z410(M + H) + ;
Anal. Calcd. for C23H31N5O2: C, 67.46; H, 7.63; N, 17.10. Found: C, 67.18; H, 7.37; N,
5 17.14.
Example 126
N-{3-[4-amino-2-ethyl-l-(tetrahydro-2^
yl]propyl} -N-isopropylurea
O
10 7-(3-Aminopropyl)-2-ethyl-l-(tetrahydro-2^-pyran^-ylmethyl)4//-imidazo[4,5-
c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and isopropyl
isocyante (128 mg, 1.5 mmol) were combined in dichloromethane (50 mL) at 0 °C and the
reaction was stirred for approximately 18 hours. Aqueous sodium carbonate (1%, 50 mL)
was added and the reaction mixture was stirred for one additional hour. The fractions were
15 separated and the aqueous fraction was extracted with chloroform (3x 20 mL). The
combined organic fractions were sequentially dried (MgS0 4 ), filtered and purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:
chloroform gradient, 0-20% CMA over 2000 mL). The desired product was further
purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting
20 with 1 0% methanol in dichloromethane over 1 500 mL). A final purification by
recrystallization from acetonitrile provided 142 mg of A/-{3-[4-amino-2-ethyl-l-
(tetrahydro-2/f-pyran-4-ylmethyl)-l//-imidazo[4,5-c]quinolin-7-yl]propyl}-iV-
isopropylurea as a white solid, mp 213-216 °C.
'H NMR (500 MHz, DMSO-rf 5 ) 5 7.93 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 1.6 Hz, 1H), 7.13
25 (dd,7= 8.4, 1.7 Hz, 1H), 6.40 (br s, 2H), 5.76 (t, J= 5.6 Hz, 1H), 5.61 (d, J= 7.7 Hz, 1H),
4.40 (d, J= 7.0 Hz, 2H), 3.82 (m, 2H), 3.65 (m, 1H), 3.16 (m, 2H), 3.02 (m, 2H), 2.93 (q,
J= 7.4 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H), 2.09 (m, 1H), 1.73 (m, 2H), 1.51-1.40 (m, 4H),
1.37 (t, J= 7.4 Hz, 3H), 1.02 (d, J= 6.5 Hz, 6H);
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13 CNMR(125 MHz,DMSO-d*) 5 157.3, 154.1, 151.5, 144.7, 139.7, 132.5, 125.9, 125.1,
122.0, 119.9, 112.7, 66.4, 49.6, 40.7,38.7, 35.6, 32.4,31.5, 29.5,23.1,20.0, 11.9;
MS (ESI) rn/z 453 (M + H) + ;
Anal. Calcd. for C 25 H36N6O2-0.33H 2 O: C, 65.41; H, 8.06; N, 18.31. Found: C, 65.41; H,
5 8.26; N, 18.30.
Example 127
1 -Isobutyl-8- { [(3 -methoxybenzyl)amino]methyl} -1 iWmidazo[4,5 -c]quinolin-4-amine
10 Part A
A solution of l-isobutyl-8-vinyl4//-imidazo[4,5--c]quinolin-4-amine (500 mg, 1.9
mmol) in dichloromethane (30 mL) and methanol (5 mL) was cooled to -78 °C. Ozone
was bubbled through the solution for 10 minutes. While still cold, the reaction was purged
with oxygen for 15 minutes and dimethyl sulfide (0.7 mL, 9.4 mmol) was added. The
1 5 reaction was warmed to ambient temperature and then concentrated under reduced
pressure. The residue was dissolved in dichloromethane (50 mL) and washed with 1%
aqueous sodium carbonate (2x 15 mL). The combined aqueous fractions were extracted
with chloroform (3x 20mL) and sequentially dried (MgS0 4 ), filtered, and purified by
chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient
20 of 0-6% methanol in dichloromethane) to provide 237 mg of 4-amino-l-isobutyM//-
imidazo[4,5-c]quinoline-8-carbaldehyde as an off-white solid. MS (ESI) m/z 269 (M +
H) + .
PartB
4-Amino-l-isobutyl-l/f-imidazo[4,5-c]quinoline-8-carbaldehyde (237 mg, 0.66
25 mmol) and 3-methoxybenzylamine (100 mg, 1 .3 mmol) were combined in methanol (25
mL) and dichloromethane (1 mL). The solution was purged with nitrogen gas and a 1M
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solution of sodium cyanoborohydride in THF (2 mL) was added. The reaction was stirred
for 30 minutes. Additional sodium cyanoborohydride in THF (1M, 1 mL) was added and
the reaction was stirred for an additional 15 minutes. Aqueous sodium carbonate (1%, 0.25
mL) was added and the reaction was stirred for 7 days. The solvent was removed under
reduced pressure and approximately equal portions of chloroform and water were added.
The fractions were separated and the organic fraction was sequentially dried (MgS04),
filtered, and purified by chromatography using a HORIZON HPFC system (silica
cartridge, eluting with a CMA; chloroform gradient, 0-20% CMA). Recrystallization from
acetonitrile provided 25 mg of l-isobutyl-8-{[(3-methoxybenzyl)amino]methyl}-l/f-
imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 125-126 °C.
*H NMR (500 MHz, DMSO-tf*) 5 8.15 (s, 1H), 7.92 (d, J « 1 .2 Hz, 1H), 7.57 (d, J = 8.5
Hz, 1H), 7.41 (dd, J= 8.5, 1.7 Hz, 1H), 7.22 (t, J= 7.4 Hz, 1H), 6.95-6.92 (m, 2H), 6.79
(m, 1H), 6.46 (br s, 2H), 4.37 (d, J= 7.3 Hz, 2H), 3.82 (s, 2H), 3.73 (s, 3H), 3.71 (s, 2H),
2.69 (br s, 1H), 2.18 (septet, J= 6.8 Hz, 1H), 0.90 (d, J= 6.6 Hz, 6H);
MS (ESI) m/z 390 (M + H) + ;
Anal. Calcd. for C^yNsO: C, 70.93; H, 6.99; N, 17.98. Found: C, 70.64; H, 6.92; N,
18.01.
(2£)-344-Amino-2-ethyl-l-(tefr^
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed
solution of 7-bromo-2-ethyl-l -(tetrahydro-2//-pyran-4-ylmethyl)-li/-imidazo[4,5-
c]quinolin-4-amine (0.58 g, 1.5 mmol) in A^V-dimethylformamide (10 mL). To the
solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and
tri-or/Ao-tolylphosphine (91 mg, 0.3 mmol) in AyV-ctimethylformamide (5 mL),
triethylamine (3.0 eq. 0.6 mL), and a solution of N,N-dimethylacrylamide (178 mg, 1 .8
mmol) in AT^V-dimethylformamide (2 mL). The reaction mixture was purged with
Example 128
quinolin-7-yl]-^/, J /V-dimethylprop-2-enamide
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nitrogen. The vessel was sealed and heated at 120 °C for 18 hours. The reaction was
cooled to ambient temperature and then concentrated to dryness under reduced pressure.
The resulting solid was dissolved in dichloromethane (100 mL) and washed with saturated
aqueous potassium carbonate (50 mL). The fractions were separated and the organic
fraction was concentrated to dryness. The resulting off-white solid was purified by
chromatography using a HORIZON HPFC system, (silica cartridge, 0-15%
CMA/chloroform). A final recrystallization from acetonitrile provided 390 mg of (2£)-3-
[4-amino-2-emyl-l-(tetrahydro-2i/-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinolin-7-yl]-
Af,N-dimethylprop-2-enamide as an off-white crystalline solid, mp >260 °C.
l H NMR (500 MHz, CDC1 3 ) 8 8.01 (d, J= 8.5 Hz, 1H), 7.81 (d, J= 1 .6 Hz, 1H), 7.68
(dd, J= 8.5, 1.9 Hz, 1H), 7.56 (d, J= 15.1 Hz, 1H), 7.27 (d, 7= 15.4 Hz, 1H) 6.52 (s, 2H),
4.47-4.41 (m, 2H), 3.85-3.79 (m, 2H), 3.21-3.13 (m, 5H), 2.98-2.92 (m, 5H) 2.09 (s, 1H),
1.51-1.35 (m, 4H), 1.38 (t,J= 7.6 Hz, 3H);
MS (APCI) m/z 408 (M + H) + ;
Anal. Calcd. for C23H29N5O2: C, 67.79; H, 7.17; N, 17.19. Found: C, 67.55; H, 7.10; N,
17.05.
Example 129
3-[4-Amino-2-ethyl- 1 -(tetrahydro-2tf-pyran-4-ylmethyl)- 1 #-imidazo[4,5 -c]
quinolin-7-yl] -i\r^V-dimethylpropanamide
NH,
A glass Parr bottle was charged with 10% palladium on carbon (0.1 g) wetted with
ethanol (10 mL) and a slurry of (2£)-3-[4-amino-2-ethyl-l-(tetrahydro-2//-pyran-4-
ylmethyl)-l-ff-imidazo[4,5-c]quinolin-7-yl]-^-dimethylprop-2-enamide (0.32 g, 0.78
mmol) in methanol (200 mL). The vessel was placed on Parr apparatus, evacuated and
charged with hydrogen (55 psi). The mixture was shaken at ambient temperature for 48
hours. The reaction mixture was filtered through a 0.2 micron PTFE membrane filter and
the filter was rinsed with methanol (1 00 mL). The filtrate was concentrated to dryness
under reduced pressure. The resulting solid was recrystallized from acetonitrile to provide
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220 rag of 3-[4-amino-2-ethyl-l-(tetrahyd^
c]quinolin-7-yl]-A^-dimethylpropanamide as a white crystalline solid, mp 219-220 °C.
! H NMR (500 MHz, CDC1 3 ) 8 7.92 (d, J= 8.4 Hz, 1H), 7.45 (d, J= 1.6 Hz, 1H), 7.16 (dd,
J= 8.3, 1.6 Hz, 1H), 6.36 (s, 2H), 4.43-4.37 (m, 2H), 3.84-3.78 (m, 2H), 3.19-3.12 (m,
2H), 2.96 (s, 3H), 2.95-2.89 (m, 4H), 2.83 (s, 3H), 2.68 (t, J= 8.2 Hz, 2H), 2.08 (s, 1H),
1.51-1.34 (m, 4H), 1.37 (t, J= 7.6 Hz, 3H);
MS (APCI) in/z 410 (M + H) + ;
Anal. Calcd. for C23H31N5O2 ^0: C, 64.61; H, 7.78; N, 16.38. Found: C, 64.63; H, 7.51;
N, 16.23.
Example 130
2-Ethy l-7-[( 1 £)-3-morpholin-4-yl-3 -oxoprop- 1 -enyl]- 1 -(tetrahydro-2//-pyran
-4-ylmethyl)-l//-imidazo[4,5-c]quinolin-4-amine
NH,
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed
solution of 7-bromo-2-ethyl-l-(tetrahydro-2//-pyran-4-ylmethyl)-li/-imidazo[4
c]quinolin-4-amine (584 mg, 1.5 mmol) in A^^-dimethylformamide (10 mL). To the
solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and
tri-ortfzo-tolylphosphine (91 mg, 0.3 mmol) in AyV-dimethylformamide (5 mL),
triethylamine (0.6 mL), and a solution of 4-acryloylmorpholine (254 mg 1.8 mmol) in
WjN-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The
vessel was sealed and heated at 120 °C for 18 hours. The reaction was cooled to ambient
temperature and then concentrated to dryness under reduced pressure. The resulting solid
was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium
carbonate (50 mL). The fractions were separated and the organic fraction was
concentrated to dryness under reduced pressure. The resulting solid was purified by
chromatography using a HORIZON HPFC system (silica cartridge, 0-15%
CMA/chloroform). A final recrystallization from acetonitrile provided 345 mg of 2-ethyl-
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7-[(l^-3-morpholin-4-yl-3-oxoprop-l-enyl]-l<tetrahydro-2H-pyran-4-ylmethyl)4//-
imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp >260 °C.
'H NMR (500 MHz, CDC1 3 ) 8 8.01 (d, J= 8.5 Hz, 1H), 7.83 (d, J= 1.6 Hz, 1H), 7.70
(dd, J= 8.5, 1.6 Hz, 1H), 7.61 d, J= 15.4, 1H), 7.32 (d, J= 15.4 Hz, 1H), 6.52 (s, 2H),
4.47-4.42 (m, 2H), 3.84-3.78 (m, 2H), 3.78-3.72 (m, 2H) 3.65-3.55 (ra, 6H) 3.19-3.1 1 (m,
2H), 2.95 (q, J= 13 Hz, 2H), 2.08 (s, 1H), 1.52-1.36 (m, 4H), 1.38 (t, J= 7.6 Hz, 3H);
MS (APC1) m/z 450 (M + H) + .
Example 131
Ethyl (2E)-3-[4-amino-2-ethyl-l-(tetrahydro-2^pyran-4-ylme%l)-lH-imidazo
[4,5-c]quinolin-7-yl]prop-2-enoate
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed
solution of7-bromo-2-ethyl-l-(tetrahydro-2//-pyran-4-ylmethyl)-li : f-imidazo[4,5-
c]quinolin-4-amine (2.5 g, 6.42 mmol) in 7^,iV-dimethylformamide (50 mL). To the
solution was added in succession, a solution of palladium acetate (144 mg, 0.642 mmol)
and tri-ortfzo-tolylphosphine (390 mg, 1.28 mmol) in ^-dimethylformamide (5 mL),
triethylamine (2.7 mL) and a solution of ethyl acrylate (0.77 g, 7.7 mmol) mNJf-
dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel
was sealed and heated at 120 °C for 18 hours. The reaction was cooled to ambient
temperature and then concentrated to dryness under reduced pressure. The resulting solid
was dissolved in dichloromethane (150 mL) and washed with saturated aqueous potassium
carbonate (100 mL). The fractions were separated and the organic fraction was
concentrated to dryness under reduced pressure. The resulting off-white solid was purified
by chromatography using a HORIZON HPFC system (silica cartridge, 0-15%
CMA/chloroform). A final recrystallzation from acetonitrile provided 1 .9 g of ethyl (2£^-
3-[4-amino-2-emyl-l-(tetrahydro-2/f-pyran-4-ylmethyl)-17f-imidazo[4,5-c]quinolin-7-
yl]prop-2-enoate as an off-white crystalline solid, mp 209-210 °C.
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l U NMR (500 MHz, CDC1 3 ) 5 8.04 (d, J= 8.5 Hz, 1H), 7.84 (d, J= 1 .6 Hz, 1H), 7.77 (d,
J= 16.1 Hz, 1H), 7.64 (dd,J= 8.5, 1.6 Hz, 1H), 6.67 (d, J= 16.1 Hz, 1H), 6.62 (s, 2H),
4.48-4.41 (m, 2H), 4.25-4.18 (m, 2H) 3.85-3.78 (m, 2H) 3.20-3.13 (m, 2H), 2.95 (q, J=
7.6 Hz, 2H), 2.12-2.05 (m, 1H), 1.51-1.38 (m, 4H), 1.38 (t, J= 7.6 Hz, 3H), 1.28 (t, J=
7.3 Hz, 3H);
MS (APCI) m/z 409 (M + H) + ;
Anal. Calcd. for C23H28N4O3: C, 67.63; H, 6.91; N, 13.72. Found: C, 67.58; H, 6.71; N,
13.98.
Example 132
Emyl 3-[4-amino-2-emyl-l-(tetrafy
quinolin-7-yl]propanoate
A glass Parr bottle was charged with 10% palladium on carbon (0.2 g) wetted with
ethanol (10 mL) and a slurry of ethyl (2 J B)-3-[4-amino-2-ethyl-l-(tetrahydro-2^-pyran-4-
ylmethyl)-li/-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate (1.81 g, 4.4 mmol) in ethanol
(250 mL). The vessel was placed on a Parr apparatus, evacuated and charged with
hydrogen (55 psi). The mixture was shaken at ambient temperature for 48 hours. The
reaction mixture was filtered through a 0.2 micron PTFE membrane filter and the filter
was rinsed with ethanol (300 ml). The filtrate was concentrated to dryness under reduced
pressure. Recrystallization from acetonitrile provided 1.51 g of ethyl 3-[4-amino-2-ethyl-
1 -(tetrahydro-2#-pyran-4-ylmethyl)- l#-imidazo[4,5-c]quinolin-7-yl]propanoate as a
white crystalline solid, mp 172-173 °C.
'H NMR (500 MHz, CDCI3) 5 7.93 (d, J= 8.5 Hz, 1H), 7.44 (d, J= 1.7 Hz, 1H), 7.14
(dd, J= 8.5, 1.7 Hz, 1H), 6.40 (s, 2H), 4.43-4.37 (m, 2H), 4.08-4.02 (m, 2H), 3.84-3.78
(m, 2H), 3.18-3.1 1 (m, 2H), 2.98-2.90 (m, 4H), 2.69 (t, J= 7.6 Hz, 2H), 2.07 (m, 1H),
1.50-1.34 (m, 4H), 1.37 (t, J= 7.6 Hz, 3H), 1.15 (t, J= 7.3 Hz, 3H);
13 C NMR (125 MHz, CDC1 3 ) 5 172.7, 154.6, 152.1, 145.4, 138.9, 132.9, 126.5, 125.7,
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122.3, 120.4, 113.5, 67.0, 60.2, 50.1, 36.1, 35.3, 30.7, 30.0, 20.5, 14.5, 12.4;
MS (APCI) m/z 41 1 (M + H) + ;
Anal. Calcd. for C23H30N4O3: C, 67.29; H, 7.37; N, 13.65. Found: C, 67.25; H, 7.53; N,
13.71.
Example 133
4-Amino-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-li/-imidazo[4,5-c]
quinoline-7-carbaldehyde
A round bottom flask, equipped with a stir bar, was charged with l-[4-amino-7-
bromo-2-(ethoxymethyl)-l//-imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol (1.18 g,
3.0 mmol), 1-propanol (30 mL), potassium vinyltrifluoroborate (0.4 g, 3.0 mmol),
triethylamine (1.25 mL, 9.0 mmol) and dichloro[l,P-
bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (Pd(dppf)), (1 1
mg, 0.015 mmol). The reaction mixture was heated at 80 °C for 66 hours. The reaction
mixture was cooled to ambient temperature and then concentrated to dryness under
reduced pressure. The solid was dissolved in dichloromethane (100 mL) and washed with
saturated aqueous potassium carbonate (50mL). The fractions were separated and the
organic fraction was concentrated to dryness. The off-white solid was purified by
chromatography using a HORIZON HPFC system (silica cartridge, 0-15%
CMA/chloroform). Recrystallization from acetonitrile provided 0.31 g of l-[4-amino-2-
(ethoxymethyl)-7-vinyl-l//-imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol as an off-
white crystalline solid. MS (APCI) m/z 341 (M + H) + .
PartB
A round bottom flask was charged with l-[4-amino-2-(ethoxymethyl)-7-vinyl-lH-
imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol (0.26 g, 0.76 mmol) and
dichloromethane (100 mL). The resulting solution was cooled in a dry ice/acetone bath.
Ozone was bubbled through the reaction mixture for 10 minutes. The reaction mixture
was purged with oxygen for 5 minutes followed by a nitrogen purge for an additional 10
Part A
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minutes. A solution of triphenylphosphine (0.4 g, L52 mmol) in dichloromethane (10
mL) was added in one portion. The dry ice/acetone bath was removed and the reaction
mixture was allowed to warm to ambient temperature for 18 hours. The reaction mixture
was concentrated to dryness under reduced pressure. The resulting solid was purified by
chromatography using a HORIZON HPFC system (silica cartridge, 0-15%
CMA/chloroform). A final recrystallization from acetonitrile provided 30 mg of 4-amino-
2-(ethoxymethyl)- 1 -(2-hydroxy-2-methyIpropyl)- 1 77-imidazo [4,5 -c]quinoline-7-
carbaldehyde as an off-white crystalline solid, mp 203-205 °C.
{ H NMR (500 MHz, CDC1 3 ) 5 10.09 (s, 1H), 8.47 (d, J= 8.5 Hz, 1H), 8.1 1 (d, J= 1.6 Hz,
1H), 7.64 (dd, 8.5, 1.6 Hz, 1H), 6.85 (s, 2H), 4.92-4.85 (m, 2H), 4.89 (s, 1H), 4.71 (s,
2H) 3.53 (q, */= 7.1 Hz, 2H), 1.18 (br s, 6H), 1.14 (t, J = 6.9 Hz, 3H);
MS (APCI) m/z 343 (M + H) + ;
Anal. Calcd. for C8H22N4O3: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.13; H, 6.46; N,
16.40.
3-[4-Amino-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-liy-imidazo[4,5-c]
A round bottom flask, equipped with a stir bar, was charged with ethyl 3-[4-amino-
2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-lif-imidazo[4,5-c]quinolin-7-
yl]propanoate (1 .0 g, 2.4 mmol) and anhydrous tetrahydrofuran (20 mL). The reaction
mixture was cooled in an ice bath. Lithium aluminum hydride (92 mg, 2.4 mmol) was
added in one portion. After 2 hours additional lithium aluminum hydride (92 mg, 2.4
mmol) was added in one portion. The ice bath was removed and the reaction mixture was
allowed to warm to ambient temperature. The reaction was quenched by successive
dropwise addition of water (1 mL), 10% sodium hydroxide solution (1 mL) and water (3
mL). The reaction mixture was maintained at ambient temperature for 1 8 hours and then
diluted with diethyl ether and water. The fractions were separated and the aqueous fraction
was extracted with diethyl ether (3x25 mL). All of the organic fractions were combined
Example 134
quinolin-7-yl]propan- 1 -ol
NH 2
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and then concentrated to dryness under reduced pressure. Purification by chromatography
using a HORIZON HPFC system (silica cartridge, 0-20% CMA/chloroform) provided 0.8
g of 3-[4-amino-2-(ethoxymethyl)-l -(2-hydroxy-2-methylpropyl)-l#-imidazo[4,5-
c]quinolin-7-yl]propan-l-ol as a white crystalline solid, mp 177-178 °C.
'H NMR (500 MHz, CDC1 3 ) 5 8.21 (d, J= 8.5 Hz, 1H), 7.45 (s, 1H), 7.12 (d, J = 8.5 Hz,
1H), 6.54 (s, 2H), 4.97 (br s, 2H), 4.94 (s, 1H), 4.71 (br s, 2H), 4.54 (t, J= 5.2 Hz, 1H),
3.56 (q, J= 6.9 Hz, 2H), 3.51 (q, J= 6.3 Hz, 2H), 2.76 (t, 7= 7.7 Hz, 2H), 1.88-1.81 (m,
2H), 1.29-1.20 (m, 6H), 1.19 (t, J= 7.1 Hz, 3H)
13 CNMR(125 MHz, DMSO-d 6 ) 5 152.3, 150.8, 145.9, 140.8, 134.6, 126.1, 125.6,
121.9, 121.5, 113.6, 71.0 65.6, 65.3, 60.6, 55.2, 34.5, 32.0, 28.1, 15.4
MS (APCI) m/z 373 (M + H) + ;
Anal, calcd for C 2 oH28N403»0.3H 2 0: C, 63.57; H, 7.63; N, 14.83. Found: C, 63.71; H,
7.32; N, 14.88.
l-[4-Amino-2-(ethoxymethyl)-7-(3-morpholin-4-ylpropyl)-l/f-imidazo[4,5-c]
A stirred solution of 3-[4-amino-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-
ltf-imidazo[4,5-c]quinolin-7-yl]propan-l-ol (0.39 g, 1.05 mmol) in pyridine (10 mL) was
cooled in an ice bath. 4-Dimethylaminopyridine (12.8 mg, 0.105 mmol) and
methanesulfonic anhydride (204 mg, 1.15 mmol) were added. After stirring for one hour,
the reaction was not complete and additional methanesulfonic anhydride was added (204
mg, 1.15 mmol). After another 2 hours of stirring the reaction was still incomplete and
additional methanesulfonic anhydride was added (204 mg, 1.15 mmol). The cooling bath
was removed and the reaction was stirred for 18 hours. The reaction mixture was
concentrated to dryness under reduced pressure. The resulting solid was dissolved in
dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (25
mL). The fractions were separated and the organic fraction was concentrated to provide
Example 135
quinolin- 1 -yl]-2-methylpropan-2-ol
Part A
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0.3 g of 3-[4-amino-2-(ethoxymethyl)-l-(2-hydroxy-2-methylpropyl)-l//-imida2»[4,5-
c]quinolin-7-yl]propyl methanesulfonate as a pale gold solid. MS (APCI) m/z 451 (M +
H) + .
PartB
A round bottom flask, equipped with a stir bar, was charged with 3-[4-amino-2-
(ethoxymethyl)-lK2-hydroxy-2-methylpropyl)4//-imidazo[4,5-c]quinolin-7-yl]propyl
methanesulfonate (0.24 g, 0.53 mmol) and acetonitrile (10 mL). Morpholine (0.23 g, 2.7
mmol) was added in one portion. The reaction mixture was heated at 75 °C for 18 hours
and then cooled to ambient temperature. After concentrating under reduced pressure, the
resulting solid was dissolved in dichloromethane (50 mL) and washed with saturated
aqueous potassium carbonate (50 mL). The fractions were separated and the organic
fraction was concentrated to dryness. The solid was purified by chromatography using a
HORIZON HPFC system (silica cartridge, 0-25% CMA/chloroform). The material was
further purified by a second chromatography treatment using a HORIZON HPFC system
(silica cartridge, 10% methanol/dichloromethane). A final recrystallization from
acetonitrile provided 0.1 g of l-[4-amino-2-(ethoxymethyl)-7-(3-morpholin-4-ylpropyl)-
li/-imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol as a white crystalline solid, mp
132-133 °C.
'H NMR (500 MHz, DMSO-d tf ) 5 8.16 (d, J= 8.5 Hz, 1H), 7.39 (d, 7= 1.6 Hz, 1H), 7.07
(dd, J = 8.4, 1 .7 Hz, 1H), 6.48 (br s, 2H), 4.89 (br s, 2H), 4.87 (s, 1H), 4.65 (br s, 2H),
3.59-3.55 (m, 4H), 3.50 (q, J = 4.7 Hz, 2H), 2.69 (t, J= 7.3 Hz, 2H), 2.36-2.30 (m, 4H)
2.30 (t, J= 7.3 Hz, 2H) 1.82-1.75 (m, 2H), 1.25-1.13 (m, 6H), 1.13 (t, J= 7.3 Hz, 3H);
MS (APCI) m/z 442 (M + H) + ;
Anal, calcd for Cj^sNsOa'O.SHzO: C, 64.49; H, 8.03; N, 15.67. Found: C, 64.26; H,
8.16; N, 15.69.
Exemplary Compounds
Certain exemplary compounds, including some of those described above in the
Examples, have the following Formulas (lie, lid, He, or Ilf) and the following Ri and R 2
substituents, wherein each line of the table is matched with Formula lie, lid, He, or Ilf to
represent a specific embodiment of the invention.
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Ri
R 2
2-methylpropyl
methyl
2-hydroxy-2-methylpropyl
methyl
tetrahydro-2/f-pyran-4-ylmethyl
methyl
3 -isopropoxy propyl
methyl
2-methylpropyl
ethyl
2-hydroxy-2-methylpropyl
ethyl
tetrahydro-2#-pyran-4-ylmethyl
ethyl
3-isopropoxypropyl
ethyl
2-methylpropyl
n-propyl
2-hydroxy-2-methylpropyl
n-propyl
tetrahydro-2//-pyran-4-ylmethyl
n-propyl
3-isopropoxypropyl
n-propyl
2-methylpropyl
n-butyl
2-hydroxy-2-methylpropyl
n-butyl
tetrahydro-2#-pyran-4-ylmethyl
n-butyl
3 -isopropoxypropyl
n-butyl
2-methylpropyl
2-methoxyethyl
2-hydroxy-2-methylpropyl
2-methoxyethyl
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Ri
R 2
tetrahydro-2#-pyran-4-ylmethyl
2-methoxyethyl
3-isopropoxypropyl
2-methoxyethyl
2-methylpropyl
ethoxymethyl
2-hydroxy-2-methylpropyl
ethoxymethyl
tetrahydro-2i/-pyran-4-ylmethyl
ethoxymethyl
3-isopropoxypropyl
ethoxymethyl
2-methylpropyl
2-hydroxyethyl
2-hydroxy-2-methylpropyl
2-hydroxyethyl
tetrahydro-2#-pyran-4-ylmethyl
2-hydroxyethyl
3-isopropoxypropyl .
2-hydroxyethyl
2-methylpropyl
hydroxymethyl
2-hydroxy-2-methylpropyl
hydroxymethyl
tetrahydro-2//-pyran-4-ylmethyl
hydroxymethyl
3 -isopropoxypropy 1
hydroxymethyl
2-methylpropyl
methoxymethyl
2-hydroxy-2-methylpropyl
methoxymethyl
tetrahydro-2//-pyran-4-ylmethyl
methoxymethyl
3-isopropoxypropyl
methoxymethyl
Certain exemplary compounds, including some of those described above in the
Examples, have the following Formulas (Ili, Ilj, Ilk, Ilm, Iln, Ho, Hp, Ilq, Ilr, or lis) and
the following Ri and R.2 substituents, wherein each line of the table is matched with
5 Formula Ili, Ilj, Ilk, Ilm, Iln, Ho, Hp, Ilq, Ilr, or lis to represent a specific embodiment of
the invention.
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N
R 1
NH 2
N
N
\
R 1 O^v^
llm
Ri
R2
2-methylpropyl
hydrogen
2-methylpropyl
methyl
2-methylpropyl
ethyl
2-methylpropyl
/7-propyl
2-methylpropyl
w-butyl
2-methylpropyl
hydroxymethyl
2-methylpropyl
2-hydroxyethyl
2-methylpropyl
methoxymethyl
2-methylpropyl
ethoxymethyl
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Ri
R 2
2-methylpropyl
2-methoxyethyl
2-hydroxy-2-methylpropyl
hydrogen
2-hydroxy-2-methylpropyl
methyl
2-hydroxy-2-methylpropyl
ethyl
2-hydroxy-2-methylpropyl
w-propyl
2-hydroxy-2-methylpropyl
tt-butyl
2-hydroxy-2-methylpropyl
hydroxymethyl
2-hydroxy-2-methylpropyl
2-hydroxyethyl
2-hydroxy-2-methylpropyl
methoxymethyl
24iydroxy-2~methylpropyl
ethoxymethyl
2-hydroxy~2-methylpropyl
2-methoxyethyl
tetrahydro-2#-pyran-4-ylmethyl
hydrogen
tetrahydro-2i/-pyran-4-ylmethyl
methyl
tetrahydro-2//-pyran-4-ylmethyl
ethyl
tetrahydro-2#-pyran-4-ylmethyl
^-propyl
tetrahydro-2//-pyran-4-ylmethyl
77-butyl
tetrahydro-2//-pyran-4-ylmethyl
hydroxymethyl
tetrahydro-2#-pyran-4-ylmethyl
2-hydroxyethyl
tetrahydro-2#-pyran-4-ylmethyl
methoxymethyl
tetrahydro-2//-pyran-4-ylmethyl
ethoxymethyl
tetrahydro-2AT-pyran-4-ylmethyl
2-methoxyethyl
2-methyl-2-[(methylsulfonyl)amino]propyl
hydrogen
2-methyl-2-[(methylsulfonyl)amino]propyl
methyl
2-methyl-2-[(methylsulfonyl)amino]propyl
ethyl
2-methyl-2-[(methylsulfonyl)amino]propyl
n-propyl
2-methyl-2-[(methylsulfonyl)amino]propyl
rt-butyl
2-methyl-2-[(methylsulfonyl)amino]propyl
hydroxymethyl
2-methyl-2-[(methylsulfonyl)amino]propyl
2-hydroxyethyl
2-methyl-2-[(methylsulfonyl)amino]propyl
methoxymethyl
2-methyl-2-[(methylsulfonyl)amino]propyl
ethoxymethyl
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Ri
R 2
2-methyl-2-[(methylsulfonyl)amino]propyl
2-methoxyethyl
2- [(methylsulfonyl)amino]ethy 1
hydrogen
2-[(methylsulfonyl)amino]ethyl
methyl
2-[(methylsulfonyl)amino]ethyl
ethyl
2-[(methylsulfonyl)amino]ethyl
^-propyl
2-[(methylsulfonyl)amino]ethyl
rc-butyl
2-[(methylsulfonyl)amino]ethyl
hydroxymethyl
2-[(methylsulfonyl)amino]ethyl
2-hydroxyethyl
2-[(methylsulfonyl)amino]ethyl
methoxymethyl
2-[(methylsulfonyl)amino]ethyl
ethoxymethyl
2-[(methylsulfonyl)amino]ethyl
2-methoxyethyl
4-[(methylsulfonyl)amino]butyl
hydrogen ;
4-[(methylsulfonyl)amino]butyl
methyl
4-[(methylsulfonyl)amino]butyl
ethyl
4-[(methylsulfonyl)amino]butyl
^-propyl
4- [(methylsulfonyl)aminojbuty 1
fl-butyl
4- [(methy lsulfonyl)amino]buty 1
hydroxymethyl
4-[(methylsulfonyl)amino]butyl
2-hydroxyethyl
4-[(methylsulfonyl)amino]butyl
methoxymethyl
4-[(methylsulfonyl)amino]butyl
ethoxymethyl
4-[(methylsulfonyl)amino]butyl
2-methoxyethyl
2-{[(isopropylamino)carbonyl]amino}ethyl
hydrogen
2-{ [(isopropylamino)carbonyl]amino} ethyl
methyl
2- { [(isopropylamino)carbonyl] amino } ethyl
ethyl
2- { [(isopropyl amino)carbonyl] amino } ethyl
n-propyl
2- { [(isopropylamino)carbonyl]amino}ethyl
j?-butyl
2- { [(isopropylamino)carbonyl]amino} ethyl
hydroxymethyl
2- { [(isopropylamino)carbonyl]amino} ethyl
2-hydroxyethyl
2-{ [(isopropylamino)carbonyl]amino} ethyl
methoxymethyl
2-{[(isopropylamino)carbonyl]amino}ethyl
ethoxymethyl
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Ri
R 2
2- { [(isopropylamino)carbonyl]amino } ethyl
2-methoxyethyl
2-(l , 1 -dioxidoisothiazolidin-2-yl)ethyl
hydrogen
2-(l , 1 -dioxidoisothiazolidin-2-yl)ethyl
methyl
2-( 1 , 1 -dioxidoisothiazolidin-2-yl)ethyl
ethyl
2-( 1 , 1 -dioxidoisothiazolidin-2-yl)ethy 1
rc-propyl
2-( 1 , 1 ~dioxidoisothiazolidin-2-yl)ethyl
H-butyl
2-( 1 , 1 -dioxidoisothiazolidin-2-yl)ethy 1
hydroxymethyl
2-(l ,1 -dioxidoisothiazolidin-2-yl)ethyl
2-hydroxyethyl
2-(l , 1 -dioxidoisothiazolidin-2-yl)ethyl
methoxymethyl
2-(l , 1 -dioxidoisothiazolidin-2-yl)ethyl
ethoxymethyl
2-(l ,1 -dioxidoisothiazolidin-2-yl)ethyl
2-methoxyethyl
Certain exemplary compounds, including some of those described above in the
Examples, have the following Formula lit and the following R 2 and R 3 substituents,
wherein each line of the table is matched with Formula lit to represent a specific
5 embodiment of the invention,
NH,
Vr 2
N
o
t
R;
lamino)ethyl
R 2
R 3
hydrogen
2-(acetylamino)ethyl
methyl
2-(acetylamino)ethyl
ethyl
2-(acetylamino)ethyl
^-propyl
2-(acetylamino)ethyl
w-butyl
2-(acetylamino)ethyl
hydroxymethyl
2-(acetylamino)ethyl
2-hydroxyethyl
2-(acetylamino)ethyl
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R 2
R3
methoxymethyl
2-(acetylamino)ethyl
ethoxymethyl
2-(acetylamino)ethyl
2-methoxyethyl
2-(acetylamino)ethyl
hydrogen
2- [(methy lsulfonyl)amino] ethyl
methyl
2- [(methylsulfonyl)amino]ethyl
ethyl
2-[(methylsulfonyl)amino]ethyl
rc-propyl
2-[(methylsulfonyl)amino]ethyl
rc-butyl
2- [(methylsulfony l)amino] ethyl
hydroxymethyl
2- [(methylsulfony l)amino] ethyl
2-hydroxyethyl
2-[(methylsulfonyl)amino]ethyl
methoxymethyl
2-[(methylsulfonyl)amino]ethyl
ethoxymethyl
2-[(methylsulfonyl)amino]ethyl
2-methoxyethyl
2-[(methylsulfonyl)amino]ethyl
hydrogen
2- { [(isopropylamino)carbonyl]amino } ethyl
methyl
2- { [(isopropylamino)carbonyl]amino } ethyl
ethyl
2- { [(isopropylamino)carbonyl] amino } ethyl
^-propyl
2-{[(isopropylamino)carbonyl]amino}ethyl
n-butyl
2-{[(isopropylamino)carbonyl]amino}ethyl
hydroxymethyl
2- { [(isopropy lamino)c arbonyl]amino } ethyl
2-hydroxyethyl
2- { [(isopropylamino)carbonyljamino} ethyl
methoxymethyl
2- { [(isopropy lamino)carbony ljamino } ethyl
ethoxymethyl
2- { [(isopropylamino)carbonyl]amino } ethyl
2-methoxyethyl
2-{[(isopropylamino)carbonyl]amino}ethyl
hydrogen
2-(benzoylamino)ethyl
methyl
2-(benzoylamino)ethyl
ethyl
2-(benzoylamino)ethyl
^-propyl
2-(benzoylamino)ethyl
tt-butyl
2-(benzoylamino)ethyl
hydroxymethyl
2-(benzoylamino)ethyl
2-hydroxyethyl
2-(benzoylamino)ethyl
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R 2
R3
methoxymethyl
2-(benzoylamino)ethyl
ethoxymethyl
2-(benzoylamino)ethyl
2-methoxyethyl
2-(benzoylamino)ethyl
hydrogen !
2-cyanoethyl
methyl
2-cyanoethyl
ethyl
2-cyanoethyl
«-propyl
2-cyanoethyl
rc-butyl
2-cyanoethyl
hydroxymethyl
2-cyanoethyl
2-hydroxyethyl
2-cyanoethyl
methoxymethyl
2-cyanoethyl
ethoxymethyl
2-cyanoethyl
2-methoxyethyl
2-cyanoethyl
hydrogen
2-(aminocarbonyl)ethyl
methyl
2-(aminocarbonyl)ethyl
ethyl
2-(aminocarbonyl)ethyl
/?-propyl
2-(aminocarbonyl)ethyl
H-butyl
2-(aminocarbonyl)ethyl
hydroxymethyl
2-(aminocarbonyl)ethyl
2-hydroxyethyl
2-(aminocarbonyl)ethyl
methoxymethyl
2-(aminocarbonyl)ethyl
ethoxymethyl
2-(aminocarbonyl)ethyl
2-methoxyethyl
2-(aminocarbonyl)ethyl
hydrogen
2-[(pyridin-3-ylcarbonyl)amino]ethyl
methyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
ethyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
^-propyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
H-butyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
hydroxymethyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
2-hydroxyethyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
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R 2
R3
methoxymethyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
ethoxymethyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
2-methoxyethyl
2-[(pyridin-3-ylcarbonyl)amino]ethyl
Compounds of the invention have been found to modulate cytokine biosynthesis by
inducing the production of interferon a and/or tumor necrosis factor a in human cells
when tested using one of the methods described below.
CYTOKINE INDUCTION IN HUMAN CELLS
An in vitro human blood cell system is used to assess cytokine induction. Activity
is based on the measurement of interferon (a) and tumor necrosis factor (a) (IFN-a and
TNF-a, respectively) secreted into culture media as described by Testerman et. al. in
"Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of
Leukocyte Biology, 58, 365-372 (September, 1995).
Blood Cell Preparation for Culture
Whole blood from healthy human donors is collected by venipuncture into
vacutainer tubes or syringes containing EDTA. Peripheral blood mononuclear cells
(PBMC) are separated from whole blood by density gradient centrifugation using
HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham
Biosciences Piscataway, NJ). Blood is diluted 1:1 with Dulbecco's Phosphate Buffered
Saline (DPBS) or Hank's Balanced Salts Solution (HBSS). Alternately, whole blood is
placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, FL)
centrifuge frit tubes containing density gradient medium. The PBMC layer is collected
and washed twice with DPBS or HBSS and re-suspended at 4 x 1 0 6 cells/mL in RPMI
complete. The PBMC suspension is added to 96 well flat bottom sterile tissue culture
plates containing an equal volume of RPMI complete media containing test compound.
Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO
concentration should not exceed a final concentration of 1% for addition to the culture
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wells. The compounds are generally tested at concentrations ranging from 30-0.014 jiM.
Controls include cell samples with media only, cell samples with DMSO only (no
compound), and cell samples with reference compound.
Incubation
The solution of test compound is added at 60 ^iM to the first well containing RPMI
complete and serial 3 fold dilutions are made in the wells. The PBMC suspension is then
added to the wells in an equal volume, bringing the test compound concentrations to the
desired range (usually 30-0.014 jaM). The final concentration of PBMC suspension is 2 x
10 6 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then
incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
Separation
Following incubation the plates are centrifuged for 10 minutes at 1000 rpm
(approximately 200 x g) at 4°C. The cell-free culture supernatant is removed and
transferred to sterile polypropylene tubes. Samples are maintained at -30 to -70°C until
analysis. The samples are analyzed for IFN-a by ELISA and for TNF-ct by
IGEN/BioVeris Assay.
Interferon (a) and Tumor Necrosis Factor (a) Analysis
IFN-a concentration is determined with a human multi-subtype colorimetric
sandwich ELISA (Catalog Number 41 105) from PBL Biomedical Laboratories,
Piscataway, NJ. Results are expressed in pg/mL.
The TNF-a concentration is determined by ORIGEN M-Series Immunoassay and
read on an IGEN M-8 analyzer from BioVeris Corporation, formerly known as IGEN
International, Gaithersburg, MD. The immunoassay uses a human TNF-a capture and
detection antibody pair (Catalog Numbers AHC3419 and AHC3712) from Biosource
International, Camarillo, CA, Results are expressed in pg/mL.
Assay Data and Analysis
In total, the data output of the assay consists of concentration values of TNF-a and
IFN-a (y-axis) as a function of compound concentration (x-axis).
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Analysis of the data has two steps. First, the greater of the mean DMSO (DMSO
control wells) or the experimental background (usually 20 pg/mL for IFN-a and 40 pg/mL
for TNF-a) is subtracted from each reading. If any negative values result from
background subtraction, the reading is reported as " * and is noted as not reliably
detectable. In subsequent calculations and statistics, " * is treated as a zero. Second, all
background subtracted values are multiplied by a single adjustment ratio to decrease
experiment to experiment variability. The adjustment ratio is the area of the reference
compound in the new experiment divided by the expected area of the reference compound
based on the past 61 experiments (unadjusted readings). This results in the scaling of the
reading (y-axis) for the new data without changing the shape of the dose-response curve.
The reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-a,a-
dimethyl-l^-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No. 5,352,784;
Example 91) and the expected area is the sum of the median dose values from the past 61
experiments.
The minimum effective concentration is calculated based on the background-
subtracted, reference-adjusted results for a given experiment and compound. The
minimum effective concentration (jwnolar) is the lowest of the tested compound
concentrations that induces a response over a fixed cytokine concentration for the tested
cytokine (usually 20 pg/mL for IFN^-a and 40 pg/mL for TNF-a). The maximal response
is the maximal amount of cytokine (pg/ml) produced in the dose-response.
CYTOKINE INDUCTION IN HUMAN CELLS
(High Throughput Screen)
The CYTOKINE INDUCTION IN HUMAN CELLS test method described above
was modified as follows for high throughput screening.
Blood Cell Preparation for Culture
Whole blood from healthy human donors is collected by venipuncture into
vacutainer tubes or syringes containing EDTA. Peripheral blood mononuclear cells
(PBMC) are separated from whole blood by density gradient centrifiigation using
HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham
Biosciences Piscataway, NJ). Whole blood is placed in Accuspin (Sigma) or LeucoSep
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(Greiner Bio-One, Inc., Longwood, FL) centrifuge frit tubes containing density gradient
medium. The PBMC layer is collected and washed twice with DPBS or HBSS and re-
suspended at 4 x 10 6 cells/mL in RPMI complete (2-fold the final cell density). The PBMC
suspension is added to 96-well flat bottom sterile tissue culture plates.
5
Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The compounds
are generally tested at concentrations ranging from 30 - 0.014 |iM. Controls include cell
samples with media only, cell samples with DMSO only (no compound), and cell samples
1 0 with a reference compound 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-a,a-dimethyl-
lH-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91)
on each plate. The solution of test compound is added at 7.5 mM to the first well of a
dosing plate and serial 3 fold dilutions are made for the 7 subsequent concentrations in
DMSO. RPMI Complete media is then added to the test compound dilutions in order to
1 5 reach a final compound concentration of 2-fold higher (60 - 0.028 \xM) than the final
tested concentration range.
Incubation
Compound solution is then added to the wells containing the PBMC suspension
20 bringing the test compound concentrations to the desired range (usually 30 - 0.014 \xM)
and the DMSO concentration to 0.4 %. The final concentration of PBMC suspension is
2xl0 6 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then
incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
25 Separation
Following incubation the plates are centrifuged for 10 minutes at 1000 rpm
(approximately 200 g) at 4°C. 4-plex Human Panel MSD MULTI-SPOT 96-well plates
are pre-coated with the appropriate capture antibodies by MesoScale Discovery, Inc.
(MSD, Gaithersburg, MD). The cell-free culture supernatants are removed and transferred
30 to the MSD plates. Fresh samples are typically tested, although they may be maintained at
-30 to -70°C until analysis.
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Interferon-a and Tumor Necrosis Factor-a Analysis
MSD MULTI-SPOT plates contain within each well capture antibodies for human
TNF-a and human IFN-a that have been pre-coated on specific spots. Each well contains
four spots: one human TNF-a capture antibody (MSD) spot, one human IFN- a capture
5 antibody (PBL Biomedical Laboratories, Piscataway, NJ) spot, and two inactive bovine
serum albumin spots. The human TNF-a capture and detection antibody pair is from
MesoScale Discovery. The human IFN-a multi-subtype antibody (PBL Biomedical
Laboratories) captures all IFN-a subtypes except IFN-a F (IFNA21). Standards consist of
recombinant human TNF-a (R&D Systems, Minneapolis, MN) and IFN-a (PBL
10 Biomedical Laboratories). Samples and separate standards are added at the time of
analysis to each MSD plate. Two human IFN-a detection antibodies (Cat. Nos. 21 1 12 &
21 100, PBL) are used in a two to one ratio (weight: weight) to each other to determine the
IFN-a concentrations. The cytokine-specific detection antibodies are labeled with the
SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeled detection antibodies
1 5 to the wells, each well's electrochemoluminescent levels are read using MSD's SECTOR
HTS READER. Results are expressed in pg/mL upon calculation with known cytokine
standards.
Assay Data and Analysis
20 In total, the data output of the assay consists of concentration values of TNF-a or
IFN-a (y-axis) as a function of compound concentration (x-axis).
A plate-wise scaling is performed within a given experiment aimed at reducing
plate-to-plate variability associated within the same experiment. First, the greater of the
median DMSO (DMSO control wells) or the experimental background (usually 20 pg/mL
25 for IFN-a and 40 pg/mL for TNF-a) is subtracted from each reading. Negative values that
may result from background subtraction are set to zero. Each plate within a given
experiment has a reference compound that serves as a control. This control is used to
calculate a median expected area under the curve across all plates in the assay. A plate-
wise scaling factor is calculated for each plate as a ratio of the area of the reference
30 compound on the particular plate to the median expected area for the entire experiment.
The data from each plate are then multiplied by the plate-wise scaling factor for all plates.
Only data from plates bearing a scaling factor of between 0.5 and 2.0 (for both cytokines
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IFN-a, TNF-a) are reported. Data from plates with scaling factors outside the above
mentioned interval are retested until they bear scaling factors inside the above mentioned
interval The above method produces a scaling of the y-values without altering the shape
of the curve. The reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-
5 tetrahydro-a,a-dimethyl-l//-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No.
5,352,784; Example 91). The median expected area is the median area across all plates
that are part of a given experiment.
A second scaling may also be performed to reduce inter-experiment variability
(across multiple experiments). All background-subtracted values are multiplied by a
10 single adjustment ratio to decrease experiment-to-experiment variability. The adjustment
ratio is the area of the reference compound in the new experiment divided by the expected
area of the reference compound based on an average of previous experiments (unadjusted
readings). This results in the scaling of the reading (y-axis) for the new data without
changing the shape of the dose-response curve. The reference compound used is 2-[4-
15 amino-2-ethoxymethyl-6,7,8,9-tet^
yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91) and the expected area is the
sum of the median dose values from an average of previous experiments.
The minimum effective concentration is calculated based on the background-
subtracted, reference-adjusted results for a given experiment and compound. The
20 minimum effective concentration (^molar) is the lowest of the tested compound
concentrations that induces a response over a fixed cytokine concentration for the tested
cytokine (usually 20 pg/mL for IFN-a and 40 pg/mL for TNF-a). The maximal response
is the maximal amount of cytokine (pg/ml) produced in the dose-response.
25 The complete disclosures of the patents, patent documents, and publications cited
herein are incorporated by reference in their entirety as if each were individually
incorporated. Various modifications and alterations to this invention will become
apparent to those skilled in the art without departing from the scope and spirit of this
invention. It should be understood that this invention is not intended to be unduly limited
30 by the illustrative embodiments and examples set forth herein and that such examples and
embodiments are presented by way of example only with the scope of the invention
intended to be limited only by the claims set forth herein as follows.
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WHAT IS CLAIMED IS:
1 . A compound of the Formula I:
I
wherein:
R A and Rb taken together form a fused benzene ring or fused pyridine ring wherein
the benzene ring or pyridine ring is substituted by one R3 group, or substituted by one R3
group and one R group;
R 3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R 5 ,
-Z-Het,
-Z-Hef-R*, and
-Z-Het'-Y-R4;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
R f and R ir are independently selected from the group consisting of hydrogen and
non-interfering substitutents;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -0- groups;
Y is selected from the group consisting of:
-o-,
-S(O) 0 .2-,
-S(0) 2 -N(R 8 )-,
-C(R6>,
-C(R 6 )-0-,
-0-C(R6)-,
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-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R6)-N(R 8 )-,
-0-C(R6)-N(R 8 )-,
-C(R 6 )-N(OR 9 )-,
-L N-Q —
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het 1 is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
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heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxy alkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R5 is selected from the group consisting of:
-C=N;
Re is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
A is selected from the group consisting of -O, -CH 2 -, -C(O)-, -S(0)o-2-> and
-N(R4)S
Q is selected from the group consisting of a bond, -C(R6>- 5 -C(R6)-C(R6>-, ~S(0) 2 -,
-C(R6>N(R8)-W-, -S(0) 2 -N(R 8 >, -C(R 6 >0-, and -C(R6)-N(OR 9 )s
V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(R8)-C(R 6 )-, and
-S(0) r ;
W is selected from the group consisting of a bond, -C(O)-, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that when R f is heterocyclyl, then heterocyclyl is attached to the
imidazo ring by an atom in heterocyclyl other than a nitrogen atom; and
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-R4 or -Z-Y-X- Y-R4, and the Y group bonded to Z is -0-,
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-0-C(R 6 )-, -OC(0)-0-, -0-C(R6)-N(R8)-,
— V-N
wherein V is
-O-C(R<0-, R 7 , or
— N-C(R 6 )-N-W- — N
-Q—
;or
R 3 is -Z-R 5 , and R 5 is
wherein V is
-O-C(R<0-; or
R 3 is -Z-Het, -Z-Hef-R4, or -Z-Het'-Y-R^ and Z is attached to a nitrogen
atom in Het or Het 1 ;
and with the further proviso that R 3 is other than -NH 2 ;
or a pharmaceutical!)^ acceptable salt thereof.
2. The compound or salt of claim 1 wherein R A and R B taken together form a fused
benzene ring wherein the benzene ring is substituted by one R 3 group, or substituted by
one R 3 group and one R group.
3. The compound or salt of claim 1 wherein R A and R B taken together form a fused
pyridine ring wherein the pyridine ring is substituted by one R 3 group, or substituted by
one R 3 group and one R group.
4. The compound or salt of any one of claims 1 , 2, or 3 wherein R' is R\ ; wherein Ri
is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R4, and
-X-R 5 ;
with the proviso that when Ri is R4> and R4 is heterocyclyl, then heterocyclyl is
attached to the imidazo ring by an atom in heterocyclyl other than a nitrogen atom.
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5. The compound or salt of any one of claims 1 , 2, 3, or 4 as dependent on claim 1
wherein R" is R 2 ; wherein R 2 is selected from the group consisting of:
-R»,
-X-R4,
-X-Y-R4, and
-X-R 5 .
6. A compound of the Formula II:
II
wherein:
R 3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R 5 ,
-Z-Het,
-Z-Het'-Rj, and
-Z-Het'-Y-R,;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
n is 0 or 1 ;
Ri is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R,,
-X-Y-X-Y-R,, and
-X-R 5 ;
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R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R4, and
-X-R 5 ;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-0-,
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
-C(R6>,
-C(R6)-0-,
-0-C(R6)-,
-0-C(0)~0-,
-N(R 8 )-Q-,
-C(R6)-N(R8)-,
-0-C(R 6 )-N(R 8 )-,
-C(R6)-N(OR 9 )-,
_/L N-Q —
, and
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N-C(R 6 )-N
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het r is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
-N-C(R 6 ) -N-S(0) 2 _v-
v v
N-C(R 6 )-N
and
-ON;
R$ is selected from the group consisting of =0 and =S;
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R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
A is selected from the group consisting of -0-, -CH 2 -, -C(O)-, -S(0)o-2-, and
-N(R0-;
Q is selected from the group consisting of a bond, -C(R<>)-, -C(R6)-C(R<;)-, -S(0>2-,
-C(R6)-N(R 8 )-W-, -S(0) 2 -N(R 8 )-, -C(Re)-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of -C(R>)-, -O-CCR,)-, -N(R 8 )-C(R6)-, and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(O)-, and -S(0)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that when Ri is R4, and R4 is heterocyclyl, then heterocyclyl is
attached to the imidazo ring by an atom in heterocyclyl other than a nitrogen atom; and
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-Rt or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
—V-N
v P
-0-C(Rfi)-, -OC(0)-0-, -0-C(R6)-N(R 8 )-, 10 wherein V is
-IvJ-C(R 6 )-^-W- -N— R 7 -y-Q-
-0-C(R 6 )-, * 7 .or R 7 ;or
R 3 is -Z-R 5 , and R 5 is
-N-C(R 6 ) -N-S(0) 2 _v-^ \
s R i J ,or ( CH 2 )b-^ wherein Vis
-0-C(R 6 )-; or
R 3 is -Z-Het, -Z-Het'-Ri, or -Z-Het'-Y-Ri, and Z is attached to a nitrogen
atom in Het or Hef;
and with the further proviso that R3 is other than -NH 2 ;
or a pharmaceutical^ acceptable salt thereof.
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7. A compound selected from the group consisting of Formulas III, IV, V, and VI:
IV V
VI
wherein:
R 3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R 5 ,
-Z-Het,
-Z-Het*-R4, and
-Z-Het'-Y-R,;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
n is 0 or 1;
Ri is selected from the group consisting of:
-R»,
-X-R,,
-X-Y-R,,
-X-Y-X-Y-R,, and
-X-R 5 ;
R2 is selected from the group consisting of:
-R4,
-X-R),
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-X-Y-R4, and
-X-R 5 ;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-0-,
-S(0)o- 2 -,
-S(0)2-N(R8)-,
-C(R 6 )-,
-C(R 6 )-0-,
-0-C(R6)-,
-0-C(0)-0- s
-N(R8)-Q-,
-C(R6)-N(R 8 )-,
-O-C^-NCRa)-,
-C(R6)-N(OR 9 )-,
-An-q—
— V-N 4-
^ Rl ° ,and
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
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haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het 1 is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
5 haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
10 or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
1 5 heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
20 (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
25
R 6 is selected from the group consisting of =0 and =S;
R 7 is C2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
30
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
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A is selected from the group consisting of -0-, -CH2-, -C(0)-, -S(0)o-2-, and
-N(R4)s
Q is selected from the group consisting of a bond, -C(R<>)-, -C(R 6 )-C(R6)-, -S(0) 2 -,
-C(R 6 )-N(R 8 )-W-, -S(0)2-N(R8)- 5 -C(R6>0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of-CCR;)-, -O-C^)-, -N(R8)-C(R6)-, and
-S(0)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(0>2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
— V-N
V R
-0-C(R6)-, -OC(0)-0-, -0-C(R 6 )-N(R 8 )-, 10 wherein V is
-W- — N — R 7 — N-Q—
■U-C(R 6 )JJ-\N- -N— R 7 -IJ
R 7 . or R?
-0-C(R6)-, ^ ,or ;or
R 3 is -Z-R5, and R5 is
-(CH 2 ),
-N-C(Re) ~N-S(0) 2 _ V -|4 ^
R/ R 7 , 0 r (CHJt-^ wherein Vis
-0-C(R6)-; or
R 3 is -Z-Het, -Z-Het'-R4, or -Z-Het'-Y-R,, and Z is attached to a nitrogen
atom in Het or Hef;
or a pharmaceutical!)^ acceptable salt thereof.
8 . A compound of Formula VII :
HN
-N
I'M " I
r b
R A R 1
VII
wherein:
G is selected from the group consisting of:
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-C(0)-R"',
a-aminoacyl,
a-aminoacyl-a-aminoacyl,
-C(0)-0-R m ,
5 -C(0)-N(R ,, ")R m ,
-C(=NY,)-R"\
-CH(OH)-C(0)-OY,,
-CH(OC M alkyl)Y 0j
-CH 2 Y 2 , and
10 -CH(CH 3 )Y 2 ;
R" 1 and R"" are independently selected from the group consisting of Cmo alkyl,
C 3 . 7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by
one or more substituents independently selected from the group consisting of halogen,
hydroxy, nitro, cyano, carboxy, Ci^alkyl, C M alkoxy, aryl, heteroaryl, aryl-C M alkylenyl,
1 5 heteroaryl-C M alkylenyl, halo-C M alkylenyl, halo-C M alkoxy, -0-C(0)-CH 3 ,
-C(0)-0-CH 3 , -C(0)-NH 2 , -0-CH 2 -C(0)-NH 2 , -NH 2 , and -S(0) 2 -NH 2 , with the proviso
that R"" can also be hydrogen;
a-aminoacyl is an a-aminoacyl group derived from an a-amino acid selected from
the group consisting of racemic, D-, and L-amino acids;
20 Y] is selected from the group consisting of hydrogen, Cw alkyl, and benzyl;
Y 0 is selected from the group consisting of Ci^ alkyl, carboxy-Ci- 6 alkylenyl,
amino-Ci.4 alkylenyl, mono-iV-Ci.6 alkylamino-C M alkylenyl, and
di-^N-Ci^ alkylamino-CM alkylenyl;
Y 2 is selected from the group consisting of mono-N-Ci-6 alkylamino,
25 di-A^iV-Ci.6 alkylamino, morpholin-4-yl, piperidin-l-yl, pyrrolidine 1-yl, and
4-C M alkylpiperazin-l-yl;
R A and R B taken together form a fused benzene ring or fused pyridine ring wherein
the benzene ring or pyridine ring is substituted by one R 3 group, or substituted by one R 3
group and one R group;
30 R3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
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-Z-R 5 ,
-Z-Het,
-Z-Het'-R4, and
-Z-Het'-Y-R4;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
Ri is selected from the group consisting of:
-Ri,
-X-R4,
-X-Y-R4,
-X-Y-X-Y-R,, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R,, and
-X-R5;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-0-,
-S(O) 0 -2-,
-S(0)2-N(R 8 )-,
-C(R5)-,
-C(R6)-0-,
-0-C(R6>,
-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R 6 )-N(R 8 )-,
-0-C(R6)-N(R8>,
-C(R6)-N(OR 9 )-,
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3
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het' is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
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nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
^(CH 2 ) a ^
-N-C(R 6 ) -N-S(0) 2 _v-f (CH2) ^ A ;- C < R e)-^
•r A
N (CH 2 ) b -^
, and
-ON;
R6 is selected from the group consisting of =0 and =S;
R 7 is C2.7 alkylene;
10 R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
A is selected from the group consisting of -0-, -CH 2 -, -C(O)-, -S(0)o-2-, and
15 -N(R4)S
Q is selected from the group consisting of a bond, -C(R6>-, -C(R6)-C(R<5)-, -S(0>2-,
-C(R6)-N(R g )-W-, -S(0)2-N(R 8 )-, -C(R«>0-, and -C(R 6 )-N(OR 9 )-;
V is selected from the group consisting of-C(R<;)-, -0-C(Re)-, -N(Rs)-C(R6)-, and
-S(0)2-;
20 W is selected from the group consisting of a bond, -C(0)-, and -S(0)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that when R] is R4, and R4 is heterocyclyl, then heterocyclyl is
attached to the imidazo ring by an atom in heterocyclyl other than a nitrogen atom; and
with the proviso that Z is other than a bond when:
25 R 3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
—V-N
v R •
-0-C(R6)-, -OC(0)-0-, -0-C(R6)-N(Rs)-, 10 wherein V is
-N-C(R 6 )-IJ-W- -N— R 7 -N-Q-
-0-C(R6)-, ^ R 7 ,or R 7 ;or
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R 3 is -Z-R5, and R 5 is
— N— C(R 6 ) — N— S(0) 2 — v-
-(CH 2 ) a ^
(CH 2 ) b ^
wherein V is
-0-C(R6)-; or
R 3 is -Z-Het, -Z-Het'-R4, or -Z-Het'-Y-R^ and Z is attached to a nitrogen
atom in Het or Hef;
and with the further proviso that R 3 is other than -NH 2 ;
or a pharmaceutical acceptable salt thereof.
9. The compound or salt of claim 7 where the compound is Formula III:
or a pharmaceutical^ acceptable salt thereof.
1 0. The compound or salt of any one of claims 6, 7, or 9 wherein n is 0.
1 1 . The compound or salt of any one of claims 4 through 10 wherein Ri is selected
from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl,
dihydroxyalkyl, alkoxyalkylenyl, alkylsulfonylalkylenyl, -X-Y-R4> -X-R 5 , and
heterocyclylalkylenyl; wherein the heterocyclyl of the heterocyclylalkylenyl group is
optionally substituted by one or more alkyl groups; wherein X is alkylene; Y is
-N(R 8 )-C(0)-, -N(R 8 )-S(0) 2 -, -N(R 8 )-C(0)-N(R 8 )-> or
N-Q —
; R4 is alkyl, aryl,
or heteroaryl; and R5 is
-N-C(R 6 ) — N — S(0) 2
-N(R 8 )-C(0)-N
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12. The compound or salt of claim 1 1 wherein Ri is selected from the group consisting
of 2-hydroxy-2-methylpropyl, 2-methylpropyl, propyl, ethyl, methyl, 2,3-
dihydroxypropyl, 3-isopropoxypropyl, 2-phenoxyethyl, 4-[(methylsulfonyl)amino]butyl,
2-methyl-2-[(methylsulfonyl)amino]propyl, 2-(acetylamino)-2-methylpropyl, 2-
{ [(isopropylamino)carbonyl]amino} -2-methylpropyl,
4- { [(isopropylamino)carbonyl]amino } butyl, 4-(l , 1 -dioxidoisothiazolidin-2-yl)butyl,
tetrahydro-2/f-pyran-4-ylmethyl, and (2,2-dimethyl-l ,3-dioxolan-4-yl)methyl.
1 3 . The compound or salt of claim 1 1 wherein Rj is selected from the group consisting
of 2-[(methylsulfonyl)amino]ethyl, 2-(l ,1 -dioxidoisothiazolidin-2-yl)ethyl, 3-(2-
oxopyrrolidin-1 -yl)propyl, and 2-{[(isopropylamino)carbonyl]amino}ethyl.
14. The compound or salt of any one of claims 5 through 1 3 wherein R 2 is selected
from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
15. The compound or salt of claim 14 wherein R 2 is selected from the group consisting
of hydrogen, methyl, ethyl, propyl, butyl, ethoxymethyl, methoxymethyl, 2-methoxyethyl,
hydroxymethyl, and 2-hydroxyethyl.
1 6. The compound or salt of any one of claims 1 through 1 5 wherein R 3 is -Z-Y-R4 or
-Z-Y-X-Y-R,.
17. The compound or salt of claim 16 wherein R3 is -Z-Y-R4.
18. The compound or salt of claim 1 6 or 1 7 wherein Y is -N(R 8 )-Q-, and R4 is alkyl,
aryl, heteroaryl, or heterocyclyl
1 9. The compound or salt of claim 1 8 wherein Q is -CCRe)-, -S(0) 2 -, or -C(R6)-N(R 8 )-.
20. The compound or salt of claim 19 wherein Q is -C(R>)-.
21 . The compound or salt of claim 19 wherein Q is -S(0)2-.
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22. The compound or salt of claim 19 wherein Q is -C(R6)-N(Rs)-.
23. The compound or salt of claim 1 8 wherein Q is -C(R 6 )-0-.
24. The compound or salt of claim 1 8 wherein Q is -S(0) 2 -N(R 8 )-.
25. The compound or salt of claim 16 wherein R3 is -Z-Y-X-Y-R4.
26. The compound or salt of any one of claims 16, 17, or 25 wherein Y is
-C(R 6 )-N(R 8 )-, and R4 is alkyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, or
heterocyclyl.
27. The compound or salt of claim 26 wherein Y in -Y-R4 is -C(R6)-N(R8)~-
28. The compound or salt of any one of claims 1 6, 1 7, and 25 wherein -Y-R4 is
-C(0)-NH 2 .
29. The compound or salt of claim 25 wherein Y in -Z-Y- is -C(O)-, and Y in -Y-R4 is
selected from the group consisting of -C(0)-NH-, -C(O)-, and -C(0)-O.
30. The compound or salt of claim 29 wherein R4 is alkyl, with the provios that when
Y in -Y-R4 is -C(0)-NH-, then R4 can also be hydrogen.
3 1 . The compound or salt of any one of claims 25, 29, and 30 wherein X is
heterocyclylene or heterocyclylene-alkylene.
32. The compound or salt of claim 16 or 17 wherein Y is -C(O)- and R4 is
heterocyclyl.
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33. The compound or salt of claim 17 wherein Y is -C(O)-, and R4 is heterocyclyl
which is unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, hydroxy, and oxo.
34. The compound or salt of claim 17 wherein Y is -C(0)-NH-, and R4 is heterocyclyl
which is unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, hydroxy, and oxo, or R4 is alkyl which is unsubstituted
or substituted by one or more substituents independently selected from the group
consisting of hydroxy, alkoxy, heteroaryl, and heterocyclyl.
35 . The compound or salt of any one of claims 1 8 through 24, 26, 27, and 32 through
34 wherein heterocyclyl is selected from the group consisting of tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl, diazepanyl,
dihydroisoquinolin-(l#)-yl, octahydroisoquinolin-(lif)-yl, dihydroquinolin-(2#)-yl,
octahydroquinolin-(2#)-yl, dihydro-l#-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and
piperazinyl.
36. The compound or salt of claim 17 wherein Y is selected from the group consisting
of -C(0)-0-, -S(0>r, and -S(0) 2 -N(R 8 )-.
37. The compound or salt of any one of claims 1 through 15 wherein R 3 is -Z-R 5 .
38. The compound or salt of claim 37 wherein R 5 is
39. The compound or salt of claim 38 wherein V is -NH-C(O)- or -C(O)-; A is -0-,
-CH 2 -, -S-, or -SO2-; a is 1, 2, or 3; and b is 2.
40. The compound or salt of claim 37 wherein Z is alkylene, and R 5 is -C=N.
A
(CH 2 ) b ^
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41 . The compound or salt of any one of claims 1 through 1 5 wherein R 3 is -Z-Het or
-Z-Het'-I^.
5 42. The compound or salt of claim 41 wherein Het and Hef are, respectively, selected
from the group consisting of the monovalent and divalent forms of tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl, diazepanyl,
dihydroisoquinolin~(l#)-yl, octahydroisoquinolin-(l#)-yl, dihydroquinolin-(2#)-yl
1 0 octahydroquinolin-(2i7)-yl, dihydro-ltf-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and
piperazinyl, each of which is unsubstituted or substituted by one or more substitutents.
43. The compound or salt of claim 42 wherein Het is substituted by one or more
substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl,
15 hydroxyalkyleneoxyalkylenyl, dialkylamino.
44. The compound or salt of claim 41 or claim 42 wherein R4 is heterocyclyl.
45. The compound or salt of any one of claims 1 through 38 wherein Z is a bond.
20
46. The compound or salt of any one of claims 1 through 39 and 41 through 44
wherein Z is Cm alkylene or C 2 ^ alkenylene.
47. The compound or salt of any one of claims 1 through 46 wherein R3 is at the 7-
25 position.
48 . A pharmaceutical composition comprising a therapeutically effective amount of a
compound or salt of any one of claims 1 through 47 and a pharmaceutically acceptable
carrier.
30
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49. A method of inducing cytokine biosynthesis in an animal comprising administering
an effective amount of a compound or salt of any one claims 1 through 47 or the
pharmaceutical composition of claim 48 to the animal.
5 50. A method of treating a viral disease in an animal in need thereof comprising
administering a therapeutically effective amount of a compound or salt of any one of
claims 1 through 47 or the pharmaceutical composition of claim 48 to the animal.
51. A method of treating a neoplastic disease in an animal in need thereof comprising
10 administering a therapeutically effective amount of a compound or salt of any one of
claims 1 through 47 or the pharmaceutical composition of claim 48 to the animal.
52. A compound of the Formula X:
15
X
wherein:
20
R 3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-R 5 ,
-Z-Het,
-Z-Het'-R4, and
-Z-Het'-Y-R^
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
25
trifluoromethyl;
n is 0 or 1 ;
Ri is selected from the group consisting of:
-R4,
-X-R4,
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-X-Y-R4,
-X-Y-X-Y-R,, and
-X-R 5 ;
R 2 is selected from the group consisting of:
-R4,
-X-R4,
-X-Y-R,, and
-X-R 5 ;
Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-0-,
-S(0)o- 2 -,
-S(0) 2 -N(R 8 )-,
-CCRs)-,
-C(Rs)-0-,
-0-C(R6)-,
-0-C(0)-0-,
-N(R 8 )-Q-,
-C(R6)-N(R8)-,
-0-C(R6)-N(R 8 )-,
-C(R6)-N(OR 9 )-,
-C N-Q —
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— V-N
, and
N-C(Re)-N
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
Het' is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
R 5 is selected from the group consisting of:
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^(CH 2 ) a -^
A
-N-C(Re) -N-S(0) 2 _ V -|( \ -f N-C(R 6 )-N
-ON;
R 6 is selected from the group consisting of =0 and =S;
R 7 is C2.7 alkylene;
Rs is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
A is selected from the group consisting of -0-, -CH 2 -, -C(O)-, -S(0)o- 2 -, and
-NCR,)-;
Q is selected from the group consisting of a bond, -C(R<;)-, -C(R6)-C(R6)-, -S(0) 2 -,
-C(R6)-N(R8>W-, -S(0) 2 -N(R8)-, -C(R 6 )-0-, and -C(R6)-N(OR 9 )-;
V is selected from the group consisting of-CCRs)-, -O-CCRe)-, -N(Rg)-C(R«K and
-S(0) 2 -;
W is selected from the group consisting of a bond, -C(0>, and -S(0) 2 -; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-R, or -Z-Y-X-Y-R4, and the Y group bonded to Z is -0-,
— V-N
-O-C(Rfi)-, -OC(0)-0- 5 -0-C(R 6 )-N(R 8 )-, 10 wherein V is
N-C(R 6 )-N-W- -N— R 7 -N
-N-Q—
-N-C(R 6 )-N-W-
-O-CCRe)-, R7 ,or ^ R 7 ; or
R3 is -Z-R5, and R5 is
-(CH 2 ) a
-N-C(Re) -N~S(0) 2 _ V -|J .
( J \. J \
•v f R 7 j0r (CH 2 ) b -^ wherein Vis
-0-C(R 6 )-; or
R 3 is -Z-Het, -Z-Het'-Rt, or -Z-Het'-Y-R|, and Z is attached to a nitrogen
atom in Het or Hef;
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and with the further proviso that R 3 is other than -NH 2 ;
or a pharmaceutically acceptable salt thereof.
53 . A compound of the Formula XI :
XI
wherein:
R 3 is selected from the group consisting of:
-Z-Y-R4,
-Z-Y-X-Y-R4,
-Z-Rs,
-Z-Het,
-Z-Het'-R,, and
-Z-Het'-Y-R,;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and
trifluoromethyl;
n is 0 or 1 ;
Ri is selected from the group consisting of:
-R»,
-X-R4,
-X-Y-R,,
-X-Y-X-Y-R,, and
-X-R 5 ;
R2 is selected from the group consisting of:
-Rt,
-X-R,,
-X-Y-R,, and
-X-R 5 ;
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Z is selected from the group consisting of a bond, alkylene, alkenylene, and
alkynylene; wherein alkylene, alkenylene, and alkynylene can be optionally interrupted
with one or more -O- groups;
Y is selected from the group consisting of:
-0-,
-S(O) 0 .2-,
-S(0)2-N(Rg)-,
-C(Rfi)-,
-C(R 6 )-0-,
-0-C(Rs)-,
-0-C(0)-0-,
-N(R 8 )-Q-,
-COE^)^)-,
-0-C(R6)-N(R 8 )-,
-C(R6)-N(OR 9 )-,
-/L N-Q —
— V-N j-
^ Rl ° ,and
-M-cpy-N
Het is heterocyclyl which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl,
amino, alkylamino, dialkylamino, and oxo;
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Het' is heterocyclylene which can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl,
haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino,
dialkylamino, and oxo;
arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and
alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene,
or heterocyclylene, and optionally interrupted by one or more -O- groups;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
10 arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups
can be unsubstituted or substituted by one or more substituents independently selected
15 from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,
heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl,
oxo;
20 R 5 is selected from the group consisting of:
5
X is selected from the group consisting of alkylene, alkenylene, alkynylene,
-C=N;
25
R6 is selected from the group consisting of =0 and =S;
R7 is C2-7 alkylene;
Rg is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,
hydroxyalkylenyl, arylalkylenyl, and heteroarylalklenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
A is selected from the group consisting of -0-, -CH2-, -C(O)-, -S(0)o-2- 5 and
30
-N(R4)S
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Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(0>2-,
-C(R 6 )-N(R 8 )-W-, -SCOVNC^K -C^-O-, and -C(R 6 )-N(OR 9 )-;
V is selected from the group consisting of-C(R 6 )-, -0-C(R 6 )-, -N(R 8 )-C(R<0-, and
-S(0)2S
W is selected from the group consisting of a bond, -C(O)-, and -S(0)2-; and
a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
with the proviso that Z is other than a bond when:
R 3 is -Z-Y-R, or -Z-Y-X-Y-R», and the Y group bonded to Z is -0-,
— V-N
V R
-0-C(R 6 )-, -OC(0)-0-, -0-C(R6)-N(R 8 )-, 10 wherein V is
-N-C(R 6 )-^-W- -N— R 7 -tJ~Q-
-0-C(R 6 )-, R 7 ,or R 7 ;or
R3 is -Z-R5, and R5 is
-N-C(R 6 ) -N-S(0) 2 _v-|^ \
( J V J \
Rt 7 , R 7 , or MCH 2 ) b -^ wherein v is
-0-C(R 6 )-; or
R 3 is -Z-Het, -Z-Het'-R,, or -Z-Het'-Y-R|, and Z is attached to a nitrogen
atom in Het or Het';
or a pharmaceutical^ acceptable salt thereof.
195
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